Derivatives of sobetirome

ABSTRACT

Ester derivatives of sobetirome with enhanced CNS distribution are disclosed.

ACKNOWLEDGEMENT OF GOVERNMENT SUPPORT

This invention was made with the support of the United States governmentunder the terms of grant numbers RC4 DK090849 and R01 DK091539, bothawarded by the National Institutes of Health. The United Statesgovernment has certain rights to this invention.

FIELD

Generally, the field is medicinal compounds and pharmaceuticalcompositions. More specifically, the field involves derivatives ofsobetirome with improved transit to the central nervous system.

BACKGROUND

There is increasing interest in activating specific thyroid hormonesignaling pathways in the brain for the treatment of certain CNSdiseases, in particular those that involve defects in remyelination(Fourcade S et al, Mol Pharmacol 63, 1296-1303 (2003) and Baxi E G etal, Glia 62, 1513-1529 (2014); both of which are incorporated byreference herein). Thyroid hormones T4 and T3 are not suitable astherapeutics for these indications as there is no therapeutic index forT4 and T3 separating the desired therapeutic effect from adverse effectsassociated with hyperthyroidism such as tachycardia, muscle wasting, andosteoporosis (Yen P M et al, Physiol Rev 81, 1097-1142 (2001); Yen P Met al, Mol Cell Endocrinol 246, 121-127 (2006); Biondi B and Klein I,Endocrine 24, 1-13 (2004); and Klein I and Ojamaa K, Endocrinol MetabClin North Am 27, 51-62 (1998); all of which are incorporated byreference herein) This issue is potentially addressed by selectivethyromimetics which are synthetic T3 agonists that show tissue selectivethyroid hormone action (Joharapurkar A A et al, J Med Chem 55, 5649-5675(2012); incorporated by reference herein.)

Sobetirome (also known as GC-1) is an example that has been studiedextensively over the past 15 years (Scanlan T S, Heart Fail Rev 15,177-182 (2010); incorporated by reference herein). Like T3, sobetiromeaffects LDL cholesterol lowering by stimulating hepatic cholesterolclearance mechanisms, but unlike T3, does so at doses that have nodeleterious effect on heart, muscle, or bone (Grover G J et al,Endocrinology 145, 1656-1661 (2004); incorporated by reference herein).This therapeutic index supports the idea of testing sobetirome forefficacy in neurological disease models. However, distribution to theCNS is an essential property for such a thyromimetic to be useful as atherapeutic agent. Therefore sobetirome derivatives with improved CNSdistribution are needed.

SUMMARY

Ester derivatives of sobetirome with the structure:

-   -   or any pharmaceutically acceptable salt thereof, wherein R₁ is        alkyl or aryl. In further examples, R₁ is unsubstituted alkyl,        substituted alkyl, heteroalkyl, substituted heteroalkyl,        cycloalkyl, substituted cycloalkyl, heterocycloalkyl,        substituted heterocycloalkyl, substituted aryl, heteroaryl, and        substituted heteroaryl. In still further examples, R₁ can be        ethyl, ethyltrimethylamino, ethylmorpholinyl, lysinyl, valinyl,        phenylalaninyl, or glucosyl. In still further examples, R₁ can        be alkylamino such as substituted alkylamino, cycloalkylamino or        substituted cycloalkylamino. In additional examples, R₁ can be        ethylamino, ethyl(N,N,N)-trimethylamino, ethylmorpholinyl,        ethyl(N,N)-dimethylamino, 3-(N-methyl)azetidinyl,        4-pyrrolidinyl, 3-pyrrolidinyl, 2,2-dimethylethylamino,        3-(3-trifluoromethyl)azetidinyl, 2-pyrrolidinyl,        2-methylethylamino, 2-trifluoromethylamino, and        N-methylethylamino.

In particular examples, the compounds have the structure:

or any pharmaceutically acceptable salt thereof, wherein R₂ is amino oralkylamino. Examples of compounds of this structure include:

including any pharmaceutically acceptable salt thereof, including ahalide salt.Another particular example is a compound of the following structure:

Also disclosed are pharmaceutical compositions that include an effectiveamount of the described compounds as an ingredient as well as apharmaceutically acceptable carrier.

Also disclosed is the use of the compounds in the treatment ofneurodegenerative disorders such as X-linked ALD and multiple sclerosisas well as methods of treating neurodegenerative disorders.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1A is a bar graph depicting concentrations of the indicatedcompounds (ng/g) in the brain 30 minutes after intraperitonealadministration of sobetirome (compound 1) (1.5 μmol/kg) or prodrugs 7,8, 9, 11, 13, 14, 15, 16, 18 (1.5 μmol/kg) in mice.

FIG. 1B is a bar graph depicting (brain/serum) ratios of the indicatedcompounds following intraperitoneal administration of sobetirome(compound 1) (1.5 μmol/kg) or prodrugs 7, 8, 9, 11, 13, 14, 15, 16, 18(1.5 μmol/kg) in mice.

FIG. 1C is a bar graph depicting (brain/liver) ratios of the indicatedcompounds following intraperitoneal administration of Sobetirome(compound 1) (1.5 μmol/kg) or prodrugs 7, 8, 9, 11, 13, 14, 15, 16, 18(1.5 μmol/kg) in mice.

FIG. 2A is a plot of the concentrations in the brain, liver, and serum(ng/g) at the indicated time post intraperitoneal administration ofsobetirome (compound 1) (1.5 μmol/kg).

FIG. 2B is a plot of the concentrations in the brain, liver, and serum(ng/g) at the indicated time post intraperitoneal administration ofprodrug 11 (1.5 μmol/kg).

FIG. 2C is a plot of the concentrations in the brain, liver, and serum(ng/g) at the indicated time post intraperitoneal administration ofprodrug 15 (1.5 μmol/kg).

FIG. 2D is a plot of the brain/serum ratios of sobetirome (compound 1)or prodrug 11 or prodrug 15 at the indicated time post intraperitonealadministration (1.5 μmol/kg).

FIG. 3A is a bar graph depicting the concentration of the indicatedcompounds in brain (ng/g of tissue) following intraperitonealadministration (1.5 μmol/kg).

FIG. 3B is a bar graph depicting the concentration of the indicatedcompounds in serum (ng/g of tissue) following intraperitonealadministration (1.5 μmol/kg).

DETAILED DESCRIPTION Definitions

Unless specifically defined otherwise, the technical terms, as usedherein, have their normal meaning as understood in the art. Thefollowing explanations of terms and methods are provided to betterdescribe the present compounds, compositions and methods, and to guidethose of ordinary skill in the art in the practice of the presentdisclosure. It is also to be understood that the terminology used in thedisclosure is for the purpose of describing particular embodiments andexamples only and is not intended to be limiting.

As used herein, the singular terms “a,” “an,” and “the” include pluralreferents unless context clearly indicates otherwise. Similarly, theword “or” is intended to include “and” unless the context clearlyindicates otherwise. Also, as used herein, the term “comprises” means“includes.” Hence “comprising A or B” means including A, B, or A and B.

Variables such as R, including all subvariables thereof (such as R₁, R₂,etc.) used throughout the disclosure are the same variables aspreviously defined unless stated to the contrary.

Acute disseminated encephalomyelitis (ADEM): An immune-mediateddemyelinating disease of the central nervous system. ADEM usually occursfollowing a viral infection, but may also appear following vaccinationor following bacterial or parasitic infection. In some cases, ADEMdevelops spontaneously. The disease involves autoimmune demyelination,similar to multiple sclerosis, and is therefore considered a multiplesclerosis borderline disease. ADEM produces multiple inflammatorylesions in the brain and spinal cord, particularly in the white matter.The lesions are typically found in the subcortical and central whitematter and cortical gray-white junction of both cerebral hemispheres,cerebellum, brainstem, and spinal cord, but periventricular white matterand gray matter of the cortex, thalami and basal ganglia may also beinvolved. When a patient suffers more than one demyelinating episode,the disease is referred to as recurrent disseminated encephalomyelitisor multiphasic disseminated encephalomyelitis.

Acute hemorrhagic leukoencephalitis (AHL or AHLE): A hyperacute andfrequently fatal form of ADEM. This disease is also known as acutenecrotizing encephalopathy (ANE), acute hemorrhagic encephalomyelitis(AHEM), acute necrotizing hemorrhagic leukoencephalitis (ANHLE),Weston-Hurst syndrome, or Hurst's disease.

Administration: Refers to providing a compound, a prodrug of a compound,or a pharmaceutical composition comprising a compound or prodrug asdescribed herein. The compound or composition can be administered byanother person to the subject or it can be self-administered by thesubject.

Adult Refsum disease: An autosomal recessive neurological disease thatis associated with the over-accumulation of phytanic acid in cells andtissues. Adult Refsum disease is divided into the adult Refsum disease 1and adult Refsum disease 2 subtypes. Individuals with Refsum diseasepresent with neurologic damage, cerebellar degeneration, and peripheralneuropathy. Onset is most commonly in childhood/adolescence with aprogressive course, although periods of stagnation or remission occur.Symptoms also include ataxia, scaly skin (ichthyosis), difficultyhearing, and eye problems including cataracts and night blindness.

Alexander disease: A very rare, congenital demyelinating disease. Thedisease primarily affects infants and children, causing developmentaldelay and changes in physical characteristics. Alexander disease is atype of leukodystrophy.

Alkyl: a branched or unbranched saturated hydrocarbon group, such as,without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. A lower alkylgroup is a saturated branched or unbranched hydrocarbon having from 1 to6 carbon atoms (C₁₋₆alkyl). The term alkyl also encompasses cycloalkyls.Alkyl also encompasses substituted alkyls which are alkyl groups whereinone or more hydrogen atoms are replaced with a substituent such as,without limitation, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino,ester, ether, ketone, aldehyde, hydroxyl, carboxyl, cyano, amido,haloalkyl, haloalkoxy, or alkoxy. The term alkyl also encompassesheteroalkyls. A heteroalkyl contains at least one heteroatom such asnitrogen, oxygen, sulfur, or phosphorus replacing one or more of thecarbons. Substituted heteroalkyls are also encompassed by the termalkyl.

Alkylamino: a heteroalkyl wherein one or more of the carbon atoms isreplaced with a nitrogen. An alkylamino can be a straight chain,branched or cycloalkylamino. An alkylamino generally has the structure—NX₁X₂ or —NX₁X₂X₃ ⁺ in which X₁, X₂, and X₃ are selected from H, asubstituted alkyl, or an unsubstituted alkyl, as that term is definedabove, provided that the group does not have the structure —NH₂ or —NH₃⁺ Examples of alkylamino groups include the following structures:—NHCH₃, —N(CH₃)₂—NH(CH₃)₂ ⁺—N(CH3)₃ ⁺, NHCH₂CH₃, NH₂CH₂CH₃ ⁺,NCH₃CH₂CH₃, N(CH₂CH₃)₂, NHCH₃CH₂CH₃ ⁺. Alkylamino also encompassesheteroalkyls in which one or more of the carbon atoms is replaced with anitrogen and, in addition, one or more of the other carbon atoms isreplaced with another heteroatom such as oxygen, sulfur or phosphorus.

The term alkylamino also contemplates alkyl groups bonded to thenitrogen forming a bond with non-terminal carbons to form acycloalkylamino structure, for example X₁NHX₃ wherein X₁ and X₃ arealkyl groups that form a covalent bond with one another. These include4-member single nitrogen (azetidinyl), 5-member single nitrogen(pyrrolidinyl), or 6-member single nitrogen (piperidinyl) structures aswell as double nitrogen structures, substituted cycloalkylaminostructures, including X₁NX₂X₃ wherein X₁ and X₃ form a covalent bond andX₂ is alkyl. Alkylamino groups are further exemplified by a CH₂CH₂—NHR₂structure wherein R₂ is ethyl and forms a covalent bond with the firstcarbon to form a 4-member ring. Such a structure is exemplified bycompound 15.

Alzheimer's disease: The most common form of dementia. Symptoms ofAlzheimer's disease include memory loss, confusion, irritability,aggression, mood swings and trouble with language. This disease ischaracterized by the loss of neurons and synapses in the cerebral cortexand certain subcortical regions. The loss results in gross atrophy ofthe affected regions, including degeneration in the temporal lobe, andparts of the frontal cortex and cingulate gyrus. Amyloid plaques andneurofibrillary tangles are visible by microscopy in brains of thoseafflicted with this disease. The cause of Alzheimer's disease isunknown; however, several hypotheses exist, including that the diseaseis caused by age-related myelin breakdown in the brain.

Amide: a group with the structure —CONX₁X₂, wherein X₁ and X₂ are H oran organic group such as an alkyl or aryl group.

Aryl: any carbon-based aromatic group including, but not limited to,benzene, naphthalene, and phenyl. The term aryl also contemplatessubstituted aryls in which one or more of the hydrogens is substitutedwith one or more groups including but not limited to alkyl, alkynyl,alkenyl, aryl, halide, nitro, amino, ester, ether, ketone, aldehyde,hydroxy, carboxylic acid, cyano, amido, haloalkyl, haloalkoxy, oralkoxy. The term aryl also contemplates heteroaryls in which one or moreof the carbons is replaced by a heteroatom. Examples of heteroatomsinclude, but are not limited to, nitrogen, oxygen, sulfur, andphosphorous. Substituted heteroaryls are also encompassed by the termaryl.

Balo concentric sclerosis: A demyelinating disease similar to standardmultiple sclerosis, but with the particularity that the demyelinatedtissues form concentric layers. Patients with this disease can surviveand/or have spontaneous remission. Typically, the clinical course isprimary progressive, but a relapsing-remitting course has been reported.

Canavan disease: An autosomal recessive degenerative disorder thatcauses progressive damage to nerve cells in the brain. Canavan diseaseis a leukodystrophy and is one of the most common degenerative cerebraldiseases of infancy. This disease is also called Canavan-VanBogaert-Bertrand disease, aspartoacylase deficiency and aminoacylase 2deficiency.

Central pontine myelinolysis (CPM): A neurologic disease caused bysevere damage of the myelin sheath of nerve cells in the brainstem, moreprecisely in the area termed the pons. The most common cause is therapid correction of low blood sodium levels (hyponatremia). Frequentlyobserved symptoms in this disorder are sudden para or quadraparesis,dysphagia, dysarthria, diplopia and loss of consciousness. The patientmay experience locked-in syndrome where cognitive function is intact,but all muscles are paralyzed with the exception of eye blinking.

Cerebral palsy: A term used for a group of permanent, non-progressivemovement disorders that cause physical disability. Cerebral palsy iscaused by damage to the motor control centers of the developing brainand can occur during pregnancy, during childbirth, or after birth up toabout age three. Patients with cerebral palsy exhibit damage to myelinsheaths.

Cerebrotendineous xanthomatosis: An inherited disorder associated withthe deposition of a form of cholesterol (cholestanol) in the brain andother tissues and with elevated levels of cholesterol in plasma but withnormal total cholesterol level. It is characterized by progressivecerebellar ataxia beginning after puberty and by juvenile cataracts,juvenile or infantile onset chronic diarrhea, childhood neurologicaldeficit, and tendineous or tuberous xanthomas. This disorder is anautosomal recessive form of xanthomatosis. It falls within a group ofgenetic disorders called the leukodystrophies.

Chronic inflammatory demyelinating polyneuropathy (CIDP): An acquiredimmune-mediated inflammatory disorder of the peripheral nervous system.The disorder is sometimes called chronic relapsing polyneuropathy (CRP)or chronic inflammatory demyelinating polyradiculoneuropathy (because itinvolves the nerve roots). CIDP is closely related to Guillain-Barrésyndrome and it is considered the chronic counterpart of that acutedisease. Its symptoms are also similar to progressive inflammatoryneuropathy. An asymmetrical variant of CIDP is known as Lewis-Sumnersyndrome. The pathologic hallmark of the disease is loss of the myelinsheath.

Cycloalkyl: a non-aromatic carbon-based ring composed of at least threecarbon atoms. Examples of cycloalkyl groups include, but are not limitedto, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkylsalso encompass substituted cycloalkyls and heterocycloalkyls where atleast one of the carbon atoms is replaced with a heteroatom such asnitrogen, sulfur or phosphorus. A heterocycloalkyl wherein one or moreof the carbons is replaced with nitrogen is also termed acycloalkylamino herein. The term also encompasses substitutedheterocycloalkyls.

Demyelinating disease: Includes any disease of the nervous system inwhich myelin is damaged or lost, or in which the growth or developmentof the myelin sheath is impaired. Demyelination inhibits the conductionof signals in the affected nerves, causing impairment in sensation,movement, cognition, or other functions for which nerves are involved.Demyelinating diseases have a number of different causes and can behereditary or acquired. In some cases, a demyelinating disease is causedby an infectious agent, an autoimmune response, a toxic agent ortraumatic injury. In other cases, the cause of the demyelinating diseaseis unknown (“idiopathic”) or develops from a combination of factors.

Derivative: a compound or portion of a compound that is derived from oris theoretically derivable from a parent compound.

Devic's syndrome: An autoimmune, inflammatory disorder in which aperson's immune system attacks the optic nerves and spinal cord, whichresults in inflammation of the optic nerve (optic neuritis) and thespinal cord (myelitis). Spinal cord lesions lead to varying degrees ofweakness or paralysis in the legs or arms, loss of sensation, and/orbladder and bowel dysfunction. Although inflammation may also affect thebrain, the lesions are different from those observed in MS. Devic'ssyndrome is similar to MS in that the body's immune system attacks themyelin surrounding nerve cells. Unlike standard MS, the attacks are notbelieved to be mediated by the immune system's T cells but rather byantibodies called NMO-IgG. These antibodies target a protein calledaquaporin 4 in the cell membranes of astrocytes which acts as a channelfor the transport of water across the cell membrane. Devic's syndrome isalso known as Devic's syndrome or neuromyelitis optica (NMO).

Diffuse myelinoclastic sclerosis: An uncommon neurodegenerative diseasethat presents clinically as pseudotumoral demyelinating lesions. Itusually begins in childhood, affecting children between 5 and 14 yearsold; however, cases in adults are possible. This disease is consideredone of the borderline forms of MS and is sometimes referred to asSchilder's disease.

Effective amount: a quantity of a specified agent sufficient to achievea desired effect in a subject being treated with that agent. Ideally, aneffective amount of an agent is an amount sufficient to inhibit or treatthe disease without causing substantial toxicity in the subject. Theeffective amount of an agent will be dependent on the subject beingtreated, the severity of the affliction, and the manner ofadministration of the pharmaceutical composition. Methods of determiningan effective amount of the disclosed compound sufficient to achieve adesired effect in a subject will be understood by those of skill in theart in light of this disclosure.

Encephalomyelitis: Inflammation of the brain and spinal cord.

Ester: a group with the structure —COOX where X is alkyl. For example anethyl ester has the structure —COOCH₂CH₃.

Experimental autoimmune encephalomyelitis (EAE): An animal model of MS(for example, see Gold et al, Brain 129, 1953-1971 (2006). EAE animalsexhibit characteristic plaques of tissue injury disseminated throughoutthe central nervous system. Plaques show infiltration of nervous tissueby lymphocytes, plasma cells, and macrophages, which cause destructionof the myelin sheaths that surround nerve cell axons in the brain andspinal cord. In some cases, EAE is induced by immunization ofsusceptible animals, such as mice, rats, guinea pigs, or non-humanprimates, with either myelin or various components of myelin. Forexample, EAE can be induced by immunization with components of themyelin sheath, such as myelin basic protein, proteolipid protein, ormyelin oligodendrocyte glycoprotein (MOG). EAE is a useful and widelyaccepted model for studying mechanisms of autoimmune CNS tissue injuryand for testing potential therapies for MS. EAE also includes “passiveEAE” which is induced in the same manner in donor animals, but involvesthe transfer of activated T-cells harvested from the donor animal'slymph nodes to naïve recipient animals.

Guillain-Barré syndrome: An acute polyneuropathy, a disorder affectingthe peripheral nervous system. Ascending paralysis, weakness beginningin the feet and hands and migrating towards the trunk, is the mosttypical symptom, and some subtypes cause change in sensation or pain, aswell as dysfunction of the autonomic nervous system. It can causelife-threatening complications, in particular if the respiratory musclesare affected or if the autonomic nervous system is involved. Thisdisease is usually triggered by an infection. Acute inflammatorydemyelinating polyneuropathy (AIDP) is the most common subtype of thisdisease. Other subtypes of Guillain-Barré syndrome include MillerFischer syndrome, acute motor axonal neuropathy (Chinese paralyticsyndrome), acute motor sensory axonal neuropathy, acute panautonomicneuropathy, and Bickerstaff's brainstem encephalitis.

Heterocycle: A group that encompasses both heteroaryls andheterocycloalkyls heterocycles may be monocyclic or polycyclic rings.Exemplary heterocycles include, but are not limited to, azepinyl,aziridinyl, azetyl, azetidinyl, diazepinyl, dithiadiazinyl,dioxazepinyl, dioxolanyl, dithiazolyl, furanyl, isooxazolyl,isothiazolyl, imidazolyl, morpholinyl, oxetanyl, oxadiazolyl, oxiranyl,oxazinyl, oxazolyl, piperazinyl, pyrazinyl, pyridazinyl, pyrimidinyl,piperidyl, piperidino, pyridyl, pyranyl, pyrazolyl, pyrrolyl,pyrrolidinyl, thiatriazolyl, tetrazolyl, thiadiazolyl, triazolyl,thiazolyl, thienyl, tetrazinyl, thiadiazinyl, triazinyl, thiazinyl,thiopyranyl, furoisoxazolyl, imidazothiazolyl, thienoisothiazolyl,thienothiazolyl, imidazopyrazolyl, cyclopentapyrazolyl, pyrrolopyrrolyl,thienothienyl, thiadiazolopyrimidinyl, thiazolothiazinyl,thiazolopyrimidinyl, thiazolopyridinyl, oxazolopyrimidinyl,oxazolopyridyl, benzoxazolyl, benzisothiazolyl, benzothiazolyl,imidazopyrazinyl, purinyl, pyrazolopyrimidinyl, imidazopyridinyl,benzimidazolyl, indazolyl, benzoxathiolyl, benzodioxolyl,benzodithiolyl, indolizinyl, indolinyl, isoindolinyl, furopyrimidinyl,furopyridyl, benzofuranyl, isobenzofuranyl, thienopyrimidinyl,thienopyridyl, benzothienyl, cyclopentaoxazinyl, cyclopentafuranyl,benzoxazinyl, benzothiazinyl, quinazolinyl, naphthyridinyl, quinolinyl,isoquinolinyl, benzopyranyl, pyridopyridazinyl and pyridopyrimidinylgroups. The term also contemplates substituted heterocycles, includingsubstituted forms of all the species above.

Hemorrhage: Bleeding or escape of blood from a vessel.

Hypoxia: The lack of oxygen supply to the tissues of the body below thenormal level.

Idiopathic inflammatory demyelinating disease (IIDD): A broad spectrumof central nervous system disorders that can usually be differentiatedon the basis of clinical, imaging, laboratory and pathological findings.Idiopathic inflammatory demyelinating diseases are sometimes known asborderline forms of multiple sclerosis. IIDD generally refers to acollection of multiple sclerosis variant diseases, including but notlimited to, optic-spinal MS, Devic's disease, ADEM, acute hemorrhagicleukoencephalitis, Balo concentric sclerosis, Schilder disease, Marburgmultiple sclerosis, tumefactive multiple sclerosis and solitarysclerosis.

Infantile Refsum disease: A peroxisome biogenesis disorder associatedwith deficiencies in the catabolism of very long chain fatty acids andbranched chain fatty acids (such as phytanic acid) and plasmalogenbiosynthesis. Infantile Refsum disease is a rare, autosomal recessivecongenital disorder, and one of three peroxisome biogenesis disordersthat belong to the Zellweger spectrum of peroxisome biogenesisdisorders.

Injury: Refers to any type of physical damage to cells, tissues, or thebody. In some cases, nervous system (e.g., CNS or PNS) injury results indemyelination and/or a demyelinating disease.

Ischemia: A vascular phenomenon in which a decrease in the blood supplyto a bodily organ, tissue, or part is caused, for instance, byconstriction or obstruction of one or more blood vessels. Ischemiasometimes results from vasoconstriction, thrombosis or embolism.Ischemia can lead to direct ischemic injury, tissue damage due to celldeath caused by reduced oxygen supply. In some cases, ischemia can leadto demyelination.

Krabbe disease: A rare, often fatal degenerative disorder that affectsthe myelin sheath of the nervous system. It is a form ofsphingolipidosis, as it involves dysfunctional metabolism ofsphingolipids. This condition is inherited in an autosomal recessivepattern. Krabbe disease is also known as globoid cell leukodystrophy orgalactosylceramide lipidosis.

Leber hereditary optic neuropathy: A mitochondrially inherited(transmitted from mother to offspring) degeneration of retinal ganglioncells (RGCs) and their axons that leads to an acute or subacute loss ofcentral vision; this affects predominantly young adult males.

Leukodystrophy: Refers to a group of diseases that affects the growth ordevelopment of the myelin sheath.

Leukoencephalopathy: Any of a group of diseases affecting the whitesubstance of the brain; can refer specifically to several diseasesincluding, for example, “leukoencephalopathy with vanishing whitematter” and “toxic leukoencephalopathy.” Leukoencephalopathies areleukodystrophy-like diseases.

Marburg multiple sclerosis: A condition in which the central nervoussystem has multiple demyelinating lesions with atypical characteristicsfor those of standard multiple sclerosis. This disease is a borderlineform of multiple sclerosis and is also known as tumefactive multiplesclerosis or fulminant multiple sclerosis. It is called tumefactivebecause the lesions are “tumor-like” and they mimic tumors clinically,radiologically and sometimes pathologically.

Marchiafava-Bignami disease: A progressive neurological diseasecharacterized by corpus callosum demyelination and necrosis andsubsequent atrophy. It is classically associated with chronicalcoholics.

Metachromatic leukodystrophy (MLD): A lysosomal storage disease that iscommonly listed in the family of leukodystrophies, as well as in thesphingolipidoses as it affects the metabolism of sphingolipids. MLD isdirectly caused by a deficiency of the enzyme arylsulfatase A.

Multifocal motor neuropathy (MMN): A progressively worsening conditionwhere muscles in the extremities gradually weaken. This disorder, amotor neuropathy syndrome, is sometimes mistaken for amyotrophic lateralsclerosis (ALS) because of the similarity in the clinical picture,especially if muscle fasciculations are present. MMN is usuallyasymmetric and is thought to be autoimmune.

Multiple sclerosis (MS): A slowly progressive CNS disease characterizedby disseminated patches of demyelination in the brain and spinal cord,resulting in multiple and varied neurological symptoms and signs,usually with remissions and exacerbation. The cause of MS is unknown butan immunological abnormality is suspected. An increased family incidencesuggests genetic susceptibility, and women are somewhat more oftenaffected than men. The symptoms of MS include weakness, lack ofcoordination, paresthesias, speech disturbances, and visualdisturbances, most commonly double vision. More specific signs andsymptoms depend on the location of the lesions and the severity anddestructiveness of the inflammatory and sclerotic processes.Relapsing-remitting multiple sclerosis (RRMS) is a clinical course of MSthat is characterized by clearly defined, acute attacks with full orpartial recovery and no disease progression between attacks.Secondary-progressive multiple sclerosis (SPMS) is a clinical course ofMS that initially is relapsing-remitting, and then becomes progressiveat a variable rate, possibly with an occasional relapse and minorremission. Primary-progressive multiple sclerosis (PPMS) presentsinitially in the progressive form. A clinically isolated syndrome is thefirst neurologic episode, which is caused by inflammation/demyelinationat one or more sites in the CNS. Progressive-relapsing multiplesclerosis (PRMS) is a rare form of MS (^(˜)5%) characterized by asteadily worsening disease state from onset, with acute relapses but noremissions.

Myelin: A lipid substance forming a sheath (known as the myelin sheath)around the axons of certain nerve fibers. Myelin is an electricalinsulator that serves to speed the conduction of nerve impulses in nervefibers. “Myelination” (also “myelinization”) refers to the developmentor formation of a myelin sheath around a nerve fiber. Similarly,“remyelination” (also, “remyelinization”) refers to the repair orreformation of the myelin sheath, such as following injury, exposure toa toxic agent, or an inflammatory response, or during the course of ademyelinating disease.

Neurodegenerative disease: Refers to any type of disease that ischaracterized by the progressive deterioration of the nervous system.

Neuropathy: A functional disturbance or pathological change in theperipheral nervous system. Axonal neuropathy refers to a disorderdisrupting the normal functioning of the axons.

Paraproteinemic demyelinating polyneuropathy: A type of peripheralneuropathy characterized by auto antibodies directed against myelinassociated glycoproteins (MAG). Anti-MAG antibodies inhibit theproduction of myelin, thereby leading to neuropathy.

Pelizaeus-Merzbacher disease (PMD): A rare central nervous systemdisorder in which coordination, motor abilities, and intellectualfunction are delayed to variable extents. The disease is one in a groupof genetic disorders collectively known as leukodystrophies.

Peroneal muscular atrophy (PMA): A genetically and clinicallyheterogeneous group of inherited disorders of the peripheral nervoussystem characterized by progressive loss of muscle tissue and touchsensation across various parts of the body. This disease is also knownas Charcot-Marie-Tooth disease (CMT), Charcot-Marie-Tooth neuropathy andhereditary motor and sensory neuropathy (HMSN).

Pharmaceutical composition: A composition containing one or more of thecompounds described herein, or a pharmaceutically acceptable saltthereof, formulated with a pharmaceutically acceptable carrier, whichcan also include other additives, and manufactured or sold with theapproval of a governmental regulatory agency as part of a therapeuticregimen for the treatment of disease in a mammal. Pharmaceuticalcompositions can be formulated, for example, for oral administration inunit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup);for topical administration (e.g., as a cream, gel, lotion, or ointment);for intravenous administration (e.g., as a sterile solution free ofparticulate emboli and in a solvent system suitable for intravenoususe); or in any other formulation described herein.

Pharmaceutically acceptable carrier: Any ingredient other than thedisclosed compounds, or a pharmaceutically acceptable salt thereof(e.g., a carrier capable of suspending or dissolving the activecompound) and having the properties of being nontoxic andnon-inflammatory in a patient. Excipients may include, for example:antiadherents, antioxidants, binders, coatings, compression aids,disintegrants, dyes (colors), emollients, emulsifiers, fillers(diluents), film formers or coatings, flavors, fragrances, glidants(flow enhancers), lubricants, preservatives, printing inks, sorbents,suspensing or dispersing agents, sweeteners, or waters of hydration.Exemplary excipients include, but are not limited to: butylatedhydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic),calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone,citric acid, crospovidone, cysteine, ethylcellulose, gelatin,hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose,magnesium stearate, maltitol, mannitol, methionine, methylcellulose,methyl paraben, microcrystalline cellulose, polyethylene glycol,polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben,retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch(corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide,vitamin A, vitamin E, vitamin C, and xylitol.

Pharmaceutically acceptable salt: Salts prepared by conventionalmethods. These include basic salts of inorganic and organic acids, suchas, without limitation, hydrochloric acid, hydrobromic acid, sulfuricacid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malicacid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid,fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid,phenylacetic acid, and mandelic acid. “Pharmaceutically acceptablesalts” of the presently disclosed compounds also include those formedfrom cations such as, without limitation, sodium, potassium, aluminum,calcium, lithium, magnesium, zinc, and from bases such as ammonia,ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine,choline, N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine,procaine, N-benzylphenethylamine, diethylamine, piperazine,tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.These salts may be prepared by standard procedures, for example byreaction of the free acid with a suitable organic or inorganic base. Anychemical compound recited in this specification may alternatively beadministered as a pharmaceutically acceptable salt thereof.Pharmaceutically acceptable salts are also inclusive of the free acid,base, and zwitterionic forms of the disclosed compounds. Descriptions ofexemplary pharmaceutically acceptable salts can be found in Stahl andWermuth, Eds., Handbook of Pharmaceutical Salts; Properties, Selectionand Use, Wiley VCH (2008). When the compounds disclosed herein includean acidic group such as a carboxy group, then suitable pharmaceuticallyacceptable cation pairs for the carboxy group are well known to thoseskilled in the art and include, without limitation, alkaline, alkalineearth, ammonium, and quaternary ammonium cations. Such salts are knownto those of skill in the art. Similarly when the compounds disclosedherein include a basic group such as an amino group, then suitablepharmaceutically acceptable anion pairs for the basic group aresimilarly well known and include halide, hydroxide, perhalate, halite,hypohalite, sulfate, sulfite, phosphate, phosphite, nitrate, nitrite,and others known to those of skill in the art. For additional examplesof pharmacologically acceptable salts, see Berge et al, J. Pharm. Sci.66, 1 (1977).

Progressive multifocal leukoencephalopathy (PML): A rare and usuallyfatal viral disease that is characterized by progressive damage orinflammation of the white matter of the brain in multiple locations. PMLoccurs almost exclusively in people with severe immune deficiency. Thecause of PML is a type of polyomavirus called the JC virus. The virus iswidespread, with 86% of the general population presenting antibodies,but it usually remains latent, causing disease only when the immunesystem has been severely weakened. PML is a demyelinating disease, inwhich the myelin sheath covering the axons of nerve cells is graduallydestroyed, impairing the transmission of nerve impulses. The disease mayoccur in subjects (e.g., humans) with severe immune deficiency, such astransplant patients on immunosuppressive medications or those receivingcertain kinds of medications. For example, PML has been associated withadministration of rituximab (off-label use in the treatment of multiplesclerosis). It affects the white matter, which is mostly composed ofaxons from the outermost parts of the brain (cortex). Symptoms includeweakness or paralysis, vision loss, impaired speech, and cognitivedeterioration.

Sobetirome: A synthetic diarylmethane derivative that was investigatedclinically as a potential therapeutic for hypercholesterolemia (see U.S.Pat. No. 5,883,294, which is incorporated by reference herein). Othernames for sobetirome found in the literature and regulatory filingsinclude QRX-431 and GC-1. Sobetirome is also referred to herein ascompound 1.

Subject: An animal (e.g., a mammal, such as a human). A subject to betreated according to the methods described herein may be one who hasbeen diagnosed with a neurodegenerative disease involving demyelination,insufficient myelination, or underdevelopment of a myelin sheath, e.g.,a subject diagnosed with multiple sclerosis or cerebral palsy, or one atrisk of developing the condition. Diagnosis may be performed by anymethod or technique known in the art. One skilled in the art willunderstand that a subject to be treated according to the presentdisclosure may have been subjected to standard tests or may have beenidentified, without examination, as one at risk due to the presence ofone or more risk factors associated with the disease or condition.

Transverse myelitis: A neurological disorder caused by an inflammatoryprocess of the grey and white matter of the spinal cord, leading toaxonal demyelination. Demyelination arises idiopathically followinginfections or vaccination, or due to multiple sclerosis. Symptomsinclude weakness and numbness of the limbs as well as motor, sensory,and sphincter deficits. Severe back pain may occur in some patients atthe onset of the disease.

Treatment: an intervention that ameliorates a sign or symptom of adisease or pathological condition. As used herein, the terms“treatment”, “treat” and “treating,” with reference to a disease,pathological condition or symptom, also refers to any observablebeneficial effect of the treatment. The beneficial effect can beevidenced, for example, by a delayed onset of clinical symptoms of thedisease in a susceptible subject, a reduction in severity of some or allclinical symptoms of the disease, a slower progression of the disease, areduction in the number of relapses of the disease, an improvement inthe overall health or well-being of the subject, or by other parameterswell known in the art that are specific to the particular disease. Aprophylactic treatment is a treatment administered to a subject who doesnot exhibit signs of a disease or exhibits only early signs, for thepurpose of decreasing the risk of developing pathology. A therapeutictreatment is a treatment administered to a subject after signs andsymptoms of the disease have developed.

Tropical spastic paraparesis (TSP): An infection of the spinal cord byhuman T-lymphotropic virus resulting in paraparesis, weakness of thelegs. TSP is also known as HTLV associated myelopathy or chronicprogressive myelopathy. As the name suggests, this disease is mostcommon in tropical regions, including the Caribbean and Africa.

Van der Knaap disease: A form of hereditary CNS demyelinating disease.This disease is a type of leukodystrophy and is also known asmegalencephalic leukoencephalopathy with subcortical cysts (MLC).

X-linked adrenoleukodystrophy (X-ALD, ALD, or X-linked ALD): A rare,inherited metabolic disorder that leads to progressive brain damage,mental deterioration, failure of the adrenal glands, muscle spasms,blindness and eventually death. ALD is one disease in a group ofinherited disorders called leukodystrophies. Adrenoleukodystrophyprogressively damages myelin. X-linked ALD male patients may be dividedinto 7 phenotypes: childhood cerebral (progressive neurodegenerativedecline leading to a vegetative state), adolescent (similar to childhoodcerebral form but with a slower progression), adrenomyeloneuropathy(progressive neuropathy, paraparesis, may progress to cerebralinvolvement), adult cerebral (dementia, similar progression to childhoodcerebral form), olivo-ponto-cerebellar (cerebral and brain steminvolvement), Addison disease (adrenal insufficiency), asymptomatic (noclinical presentation, subclinical adrenal insufficiency, or AMNphenotype). X-linked ALD female patients may be divided into 5phenotypes: asymptomatic (no neurologic or adrenal involvement), mildmyelopathy, moderate to severe myelopathy (similar to male AMNphenotype), cerebral (progressive dementia and decline), and adrenal(primary adrenal insufficiency). X-linked ALD patients may progress fromone phenotype to another over the course of their life. ALD is alsoknown as Addison-Schilder disease or Siemerling-Creutzfeldt disease.

Zellweger syndrome: A rare congenital disorder, characterized by thereduction or absence of functional peroxisomes in the cells of anindividual. This disease is classified as a leukodystrophy and is one ofthree peroxisome biogenesis disorders that belong to the Zellwegerspectrum of peroxisome biogenesis disorders.

Sobetirome Prodrugs

Disclosed compounds are of the formula:

wherein R₁ is alkyl or aryl. This structure includes anypharmaceutically acceptable salts of the described structure. R₁ can beany alkyl or aryl including unsubstituted alkyl, substituted alkyl,heteroalkyl, substituted heteroalkyl, cycloalkyl, substitutedcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, substitutedaryl, heteroaryl, or substituted heteroaryl. In more particularexamples, R₁ is ethyl, ethyltrimethylamino, ethylmorpholinyl, lysinyl,valinyl, phenylalaninyl, or glucosyl.

In other particular examples, R₁ is alkylamino. In these examples, R₁can be substituted alkylamino, cycloalkylamino, or substitutedcycloalkylamino. Examples of these compounds can have the structure:

wherein R₂ is amino or alkylamino. In more particular examples, thestructure is

including any pharmaceutically acceptable salt thereof, such as a halidesalt.

In still more particular examples, the structure is:

Although systemically administered sobetirome distributes predominantlyto the liver, there is indirect evidence from several prior studiesindicating that sobetirome does distribute to the CNS in a potentiallyuseful capacity (Takahashi N et al, Biol Pharm Bull 37, 1103-1108(2014); Trost S et al, Endocrinology 141, 3057-3064 (2000), Bernal J,Nat Clin Pract Endrocrinol Metab 3, 249-259 (2007); Oppenheimer J H andSchwartz H L, Endocr Rev 18, 462-475 (1997); and Bernal J, J EndocrinolInvest 25, 268-288 (2002); all of which are incorporated by referenceherein). However, quantitative data disclosed herein reveals that thebrain/serum ratio of sobetirome is 0.2 (Table 2, below), a value that isslightly below the optimum range of 0.3-1.0 for CNS drugs (Doran A etal, Drug Metab Sispos 33, 165-174 (2005) and Reichel A, Curr Drug Metab7, 183-203 (2006); both of which are incorporated by reference herein).

Disclosed herein are esters of sobetirome with improved blood brainbarrier (BBB) permeability. These structures are alcohols designed toincrease the BBB permeability of the sobetirome ester. Selected alcoholsincluded groups that were though to either enhance passive diffusionacross the BBB or facilitate active transport by BBB transporters.

Structures thought to utilize both active and passive transportmechanisms were examined. Passive transport prodrugs include a simplealkyl alcohol (compound 7), amino-alcohols (compounds 9, 11, and 15) andamino-acids (compound 14). Active transport based prodrug esters weredesigned to take advantage the presence of LAT transporters, amino-acidtransporters, glucose transporters, or choline transporters found at theBBB (Lee G et al, Pharmacol Rev 53, 569-596 (2001); incorporated byreference herein).

Compounds 7-18

The synthesis of the sobetirome prodrugs was achieved in 5 linear stepsstarting from 2-isopropylphenol and 2,6-dimethyl-4-hydroxybenzaldehyde.The major step joining the phenolic and carboxylate ends of sobetiromewas accomplished using an aryl Grignard prepared according to Knochel'sprocedure (Boymond L et al, Agnew Chem Int Ed 37, 1701-1703 (1998);incorporated by reference herein). The inner ring carboxylate (compound3) intermediate was synthesized by alkylating2,6-dimethyl-4-hydroxybenzaldehyde (compound 2) with tert-butylchloroacetate in a high yield. The phenolic portion of sobetirome(compound 1) was prepared by first iodinating 2-isopropylphenol(compound 4) at the para position using NaI and NaOCl (Edgar K J andFalling S N, J Organ Chem 55, 5287-5291 (1990), incorporated byreference herein). The phenol was then alkylated with benzyl bromideresulting in the benzyl protected phenol (compound 5). The inner-ringcarboxylate portion of sobetirome (compound 1) was synthesized byalkylating 2,6-dimethyl-4-hydroxybenzaldehyde with2-chloro-t-butylacetate resulting in (compound 5). The coupling ofcompound 5 and compound 3 was synthesized by first generating the arylGrignard reagent of compound 5 via the Knochel procedure (Boymond L etal, 1998 supra) with iPrMgCl. The aryl Grignard reagent was then cooledto −78° C. and a solution of compound 3 in THF was added. This resultedin the corresponding coupled product containing a carbinol in themethylene bridge connecting the two fragments. The carbinol and t-butylester were then removed via the actions of TFA and triethylsilane(Penning T D et al, J Med Chem 43, 721-735 (2000); incorporated byreference herein) resulting in the key intermediate compound 6 in gramquantities and a 55% overall yield for the two steps (Scheme 1)

With the phenol-protected sobetirome (compound 6) in hand, the firstprodrug synthesized was the ethyl ester version of sobetirome. The ethylester (compound 7) was synthesized by treating compound 6 withHCl(ethanol) and then deprotecting the benzyl ether with 10% Pd/C andtriethylsilane (Mandal P K and McMurray J S, J Org Chem 72, 6599-6601(2007); incorporated by reference herein). The choline prodrug (compound8) was next synthesized. After a few unsuccessful attempts atesterification of compound 6 with choline chloride and the acid chlorideof compound 6, an alkylation of compound 6 with (2-Bromoethyl)trimethylammonium bromide and K₂CO₃ was attempted (Smith N D et al,Bioorg Med Chem Lett 15, 3197-3200 (2005); incorporated by referenceherein). This resulted in the generation of the correspondingbenzyl-protected ester which was then deprotected with the same 10% Pd/Cand triethylsilane conditions giving the choline-sobetirome prodrug(compound 8) in 39% overall yield. The 4-(2-hydroxyethyl)morpholinesobetirome prodrug (compound 9) was synthesized by treating a cooledsolution of 4-(2-hydroxyethyl)morpholine, DMAP, and DCM with a solutionof the acid chloride (compound 6a) and DCM. Following the same benzyldeprotection method, this resulted in the morpholino prodrug (compound9) in a 48% yield. (Scheme 2).

The next set of sobetirome prodrugs synthesized contained anethanolamine sidechain for increasing the log P and adding a positivecharge to sobetirome or for acting as a linker to amino acids. Theethanolamine sobetirome prodrug synthesis was started in a similarmanner to that of compound 9 except boc-ethanolamine was used. Theprotected ethanolamine intermediate (compound 10) was then subjected tobenzyl deprotection conditions, followed by HCl (ethyl acetate) toremove the boc residue resulting in (compound 11) in a 37% overall yieldfor the three steps. The lysine and valine sobetirome prodrugs weresynthesized by first deprotecting the boc residue of compound 10resulting in the free primary amine (compound 12). The primary amine ofcompound 12 was then coupled with the carboxylic acid ofBoc-Lysine(Boc)-OH and Boc-Valine using EDCl, HoBt, DIEA and DMF.(Scheme 3).

Following the standard benzyl ether deprotection and boc deprotectionconditions yielded the Sobetirome-Lysine (compound 13) andSobetirome-Valine (compound 14) (Scheme 4) Lastly, theazetidine-sobetirome prodrug was designed and synthesized in an effortto examine the effect on BBB permeability of a prodrug with a secondaryalcohol versus a primary alcohol (compound 11). Following a similarsynthetic sequence as was used with compound 11, theSobetirome-Azetidine was synthesized in a 35% yield over the three steps(Scheme 5).

Additional Sobetirome-based prodrugs were all designed to utilize activetransport mechanisms to gain access to the CNS. The Sobetirome-Tyrosineprodrug was synthesized using Schotten-Baumann conditions as describedby Millar and Hare′. The acid chloride of compound 6 was slowly added toa mixture of boc-tyrosine, NaOH, acetone and water cooled to 0° C. Theresulting phenolic ester was then subjected to benzyl ether and bocdeprotection conditions yielding compound 16. The Sobetirome-Glucoseprodrug was prepared by first synthesizing benzyl2,3,4-tri-O-benzyl-beta-D-glucopyranoside (compound 17) as described inLu W et al, Carbohydr Res 340, 1213-1217 (2005); incorporated byreference herein. The ester was formed by cooling a solution of compound17, DMAP, and DCM to 0° C. and slowly adding the acid chloride generatedfrom compound 6. With the ester in hand, the five benzyl ethers weredeprotected using 100 mol % of 10% Pd/C and 60 equiv of triethylsilaneyielding compound 18 in a 44% overall yield.

Compounds 19-32

Following the biological testing of the first-generation prodrugs asecond set of prodrugs was prepared that was primarily focused aroundthe ethanolamine pro-moiety (compounds 19-32). The second-generationSobetirome-based prodrugs were synthesized using the same methodologydescribed above except that Cbz-protected amino alcohols were used forsome of the amino-alcohols instead of the standard boc-protected aminoalcohols. The use of the cbz-protecting group allowed us to perform onedeprotection (10% Pd/C, Et₃SiH) to remove both the benzyl and cbzprotecting groups. This resulted in a more stream-lined synthesis andalso avoided the troublesome acidic deprotection of the boc residue forsome of the more acid-sensitive prodrugs. Using the synthetic routedepicted in Scheme 7, additional Sobetirome-prodrugs were synthesized.

Biology

A biodistribution study in mice was performed on each prodrug todetermine the brain, liver, and serum levels of sobetirome following asystemic (intraperitoneal) administration. The mice received anequimolar dose (1.5 μmol/kg) of prodrug and one cohort received the samedose of sobetirome as a control. Tissue and blood were collected 30minutes post-injection and the concentration of sobetirome wasdetermined using an LC-MS/MS. Most of the prodrugs tested in this waydid not show increased brain sobetirome levels compared to the equimolarsystemic injection of sobetirome (FIG. 1A). However, significant brainsobetirome level increases were observed with prodrugs 11 and 15, whichare both sobetirome esters of ethanolamines. In addition to increasedbrain sobetirome levels, these two esters showed significantly lowerliver and serum sobetirome levels compared to the direct sobetiromeinjection leading to 7- and 9-fold increases compared to sobetirome inthe brain/serum sobetirome ratio for prodrugs 11 and 15, respectively(FIG. 1B). The brain/liver sobetirome ratio was increased compared tosobetirome injection by 5- and 10-fold for 11 and 15, respectively (FIG.1C)

The single time point pilot study was followed up for 11 and 15 vs.sobetirome with an 8-hour time course distribution study in mice. Apharmacokinetic study showed that the t_(1/2) of sobetirome in mice is1.5 hours indicating that an 8 hour study would be sufficient toquantify >95% of the sobetirome exposure. The sobetirome AUC, C_(max),and T_(max) values in brain, liver and serum resulting from systemicadministration of sobetirome, prodrug 11, and prodrug 15 are shown inTable 1 and the curves used to obtain these values are shown in FIGS.2A, 2B and 2C.

TABLE 1 Pharmacokinetic parameters (AUC_(0-->t) and T_(max)) ofsobetirome in mouse serum, brain, and liver tissues after administrationof sobetirome (1) (1.5 μmol/kg) or prodrugs 11 and 15 (1.5 umol/kg).Sobetirome (1) prodrug 11 prodrug 15 AUC_(0-->t) T_(max) AUC_(0-->t)T_(max) AUC_(0-->t) T_(max) Tissue (ng/g * h) (min) (ng/g *h) (min)(ng/g * h) (min) Serum 68.2 <15 36.8 <15 10.9 30 Brain 10.8 <15 17.1 <1514.3 60 Liver 293 <15 190 <15 72.4 30

The results show that the trend observed in the single time point studyis observed in the full time course also; prodrugs 11 and 15 generateincreased sobetirome exposure (compared to direct sobetirome injection)in brain and decreased sobetirome exposure in liver and serum. Thebrain/serum ratio based on AUC was found to be 0.16 for sobetiromeinjection compared to 0.46 and 1.31 for 11 and 15, respectively (Table2). Clear C_(max) and T_(max) values were obtained only for prodrug 15(Table 1) as maximal sobetirome concentrations were recorded at theinitial (15 min) time points in brain, liver, and serum for bothsobetirome and 11. In addition to improved sobetirome brain/serumratios, prodrug 15 also displayed a five-fold increase in sobetiromeAUC_((brain))/AUC_((liver)) relative to sobetirome (Table 2 and FIG.2D).

TABLE 2 Sobetirome tissue distribution values (AUC_(brain)/AUC_(serum))and (AUC_(brain)/AUC_(liver)) after ip administration of sobetirome orprodrugs 11 and 15. Sobetirome Distribution CompoundAUC_(brain)/AUC_(serum) AUC_(brain)/AUC_(liver)  1 0.2 0.037 11 0.50.090 15 1.3 0.20 

It is not clear why the disclosed prodrugs other than prodrugs 11 and 15did not improve sobetirome CNS distribution, even though each of theseseven esters had literature precedent for improving CNS distribution ofother carboxylic acid containing drugs. That prodrugs 11 and 15 were theonly two from the series that improved CNS distribution suggests thatthe ethanolamino ester is particularly well suited for this role atleast with respect to sobetirome and related carboxylic acid containingdrugs. The superior CNS distribution properties of 15 compared to 11suggests that either a secondary amine or C₁ branching is beneficialwith respect to CNS uptake, circulating ester half-life, or both. The2-morpholinoethyl ester 9 that contains a tertiary ethanolamine did notsignificantly increase sobetirome brain levels (FIG. 1A) or thebrain/serum ratio suggesting that the more highly substituted tertiaryethanolamine is not tolerated. Likewise, the structurally relatedquaternary ammonium choline ester 8 did not improve CNS distribution ofsobetirome despite reports of its successful use in promoting CNSdistribution of a carboxylate containing COX inhibitor (Smith N D et al,Bioorg Med Chem Lett 15, 3197-3200 (2005), incorporated by referenceherein). This suggests the requirement for an amino group that canshuttle between neutral and cationic forms for the mechanism involved inthe BBB transport of these sobetirome-aminoethyl ester prodrugs.

The structural characteristics of the sobetirome-azetidine prodrug(compound 15) that may contribute to its ability to increase brainconcentration of sobetirome are the presence of the secondary alcoholester linkage and the secondary amine. The branching found on thesecondary alcohol ester is hypothesized to cause the delay in time toreach C_(max)(1 hour) relative to sobetirome (compound 1) (15 min) (10).In addition, the secondary amine in prodrug 15 (c log P: 5.18) maintainsa similar c log P as Sobetirome (c log P: 4.87) and at the same timeeliminates the negative charge on Sobetirome found at physiological pH.The loss of the negative charge coupled with the slow release mechanismfound in prodrug 15 makes this a unique prodrug capable of increasingthe Sobetirome AUC_((brain))/AUC_((serum)) ratio to a value of 1.31.

Methods

Animal Studies:

Experimental protocols were in compliance with the National Institutesof Health Guide for the Care and Use of Laboratory Animals and approvedby the Oregon Health & Science University Institutional Animal Care &Use Committee. Wild type male C57Bl/6 mice, aged 8-10 weeks, were housedin a climate controlled room with a 12 hour light-dark cycle with adlibitum access to food and water. Mice were injected onceintraperitoneally (IP) with sobetirome and prodrugs at 3.05 μmol/kg.Euthanasia was performed on three mice per time points at the followingtimes (0.15 h, 0.5 h, 1 h, 2 h, 4 h, and 8 h) and the tissues and bloodwere harvested. Tissues were immediately frozen and blood was kept onice for a minimum of 30 minutes and then spun down at 7,500×G for 15minutes. Serum (100 uL) was collected and was stored with tissues at−80° C. until samples were processed.

Serum Processing:

The serum samples were warmed to room temperature and 10 μL of 2.99 μMinternal standard (D₆-Sobetirome) was added to them. Acetonitrile (500μL) was added and the sample was vortexed for 20 seconds. The sample wasthen centrifuged at 10,000×G for 15 minutes at 4° C. Next, 90% of theupper supernatant was transferred to a glass test tube and concentratedusing a speedvac for 1.5 hours at 45° C. The dried sample was thendissolved in 400 μL of 50:50 ACN:H₂O and vortexed for 20 seconds. Theresulting mixture was transferred to an Eppendorf and centrifuged at10,000×G for 15 minutes. The supernatant was filtered with 0.22 μMcentrifugal filters and submitted for LC-MS/MS analysis. The standardcurve was made with 100 μL of serum from an 8-10 week old mouse notinjected with Sobetirome or prodrug. The processing was performedexactly the same except after filtering the sample was split amongst 6vials. To 5 out of the 6 vials was added Sobetirome to make finalconcentrations in matrix of (0.1 pg/μL, 1 pg/μL, 10 pg/μL, 100 pg/μL,and 1000 pg/μL).

Brain Processing:

The brain samples were warmed to room temperature and transferred to ahomogenizer tube with 5 GoldSpec ⅛ chrome steel balls (AppliedIndustrial Technologies). The resulting tube was weighed and then 1 mLof H₂O was added, followed by 10 μL of 2.99 μM internal standard(D₆-sobetirome). The tube was homogenized with a Bead Bug® for 30seconds and then transferred to a Falcon tube containing 3 mL of ACN.ACN (1 mL) was used to wash homogenizer tube and the solution wastransferred back to the Falcon tube. The sample was then processed usingthe same method for the serum processing except the sample wasconcentrated in a glass tube using a speedvac for 4 hours at 45° C.

Liver Processing:

The liver samples were warmed to room temperature and transferred to ahomogenizer tube with 5 GoldSpec ⅛ chrome steel balls (AppliedIndustrial Technologies). The resulting tube was weighed and then 1 mLof H₂O was added, followed by 10 μL of 2.99 μM internal standard(D₆-Sobetirome). The tube was then homogenized with a Bead Bug for 30seconds. A small sample (100 μL) was then taken from the homogenizedmixture and processed. This was done because the liver levels found insome samples were too high for the LC-MS/MS instrument. The samples werethen processed using the serum processing method.

General Chemistry:

¹HNMR were taken on a Bruker 400®. All ¹HNMR were calibrated to the NMRsolvent reference peak (D₆-DMSO, CDCl₃, CD₃OD). High resolution massspectrometry (HRMS) with electrospray ionization was performed by theBioanalytical MS Facility at Portland State University. Inert atmospherereactions were performed under argon gas passed through a small columnof drierite and were conducted in flame-dried rbfs. Anhydroustetrahydrofuran (THF), dichloromethane (DCM), and dimethylformamide(DMF) were obtained from a Seca Solvent System. All other solvents usedwere purchased from Sigma-Aldrich or Fisher. Purity analysis of finalcompounds was determined to be >95% by HPLC. HPLC analysis was performedon a Varian ProStar HPLC with an Agilent Eclipse Plus® C18 5 μM column(4.6×250 mm) with a gradient of 10% to 95% acetonitrile (0.1% TFA) over15 minutes.

Pharmaceutical Compositions

The compounds disclosed herein may be included in pharmaceuticalcompositions (including therapeutic and prophylactic formulations),typically combined together with one or more pharmaceutically acceptablecarriers (known equivalently as vehicles) and, optionally, othertherapeutic ingredients.

Such pharmaceutical compositions can formulated for administration tosubjects by a variety of mucosal administration modes, including byoral, rectal, intranasal, intrapulmonary, intravitrial, or transdermaldelivery, or by topical delivery to other surfaces including the eye.Optionally, the compositions can be administered by non-mucosal routes,including by intramuscular, subcutaneous, intravenous, intra-arterial,intra-articular, intraperitoneal, intrathecal, intracerebroventricular,or parenteral routes. In other examples, the compound can beadministered ex vivo by direct exposure to cells, tissues or organsoriginating from a subject.

To formulate the pharmaceutical compositions, the compound can becombined with various pharmaceutically acceptable additives. Desiredadditives include, but are not limited to, pH control agents, such asarginine, sodium hydroxide, glycine, hydrochloric acid, citric acid, andthe like. In addition, local anesthetics (for example, benzyl alcohol),isotonizing agents (for example, sodium chloride, mannitol, sorbitol),adsorption inhibitors (for example, Tween®-80), solubility enhancingagents (for example, cyclodextrins and derivatives thereof), stabilizers(for example, serum albumin), and reducing agents (for example,glutathione) can be included.

When the composition is a liquid, the tonicity of the formulation, asmeasured with reference to the tonicity of 0.9% (w/v) physiologicalsaline solution taken as unity, is typically adjusted to a value atwhich no substantial, irreversible tissue damage will be induced at thesite of administration. Generally, the tonicity of the solution isadjusted to a value of about 0.3 to about 3.0, such as about 0.5 toabout 2.0, or about 0.8 to about 1.7. The compound can be dispersed inany pharmaceutically acceptable carrier, which can include a hydrophiliccompound having a capacity to disperse the compound, and any desiredadditives. The carrier can be selected from a wide range of suitablecompounds, including but not limited to, copolymers of polycarboxylicacids or salts thereof, carboxylic anhydrides (for example, maleicanhydride) with other monomers (for example, methyl (meth)acrylate,acrylic acid and the like), hydrophilic vinyl polymers, such aspolyvinyl acetate, polyvinyl alcohol, polyvinylpyrrolidone, cellulosederivatives, such as hydroxymethylcellulose, hydroxypropylcellulose andthe like, and natural polymers, such as chitosan, collagen, sodiumalginate, gelatin, hyaluronic acid, and nontoxic metal salts thereof.Often, a biodegradable polymer is selected as a carrier, for example,polylactic acid, poly(lactic acid-glycolic acid) copolymer,polyhydroxybutyric acid, poly(hydroxybutyric acidglycolic acid)copolymer and mixtures thereof.

Alternatively or additionally, synthetic fatty acid esters such aspolyglycerin fatty acid esters, sucrose fatty acid esters and the likecan be employed as carriers. Hydrophilic polymers and other vehicles canbe used alone or in combination, and enhanced structural integrity canbe imparted to the vehicle by partial crystallization, ionic bonding,cross-linking and the like. The carrier can be provided in a variety offorms, including fluid or viscous solutions, gels, pastes, powders,microspheres, and films for direct application to a mucosal surface.

The compound can be combined with the carrier according to a variety ofmethods, and release of the compound can be by diffusion, disintegrationof the vehicle, or associated formation of water channels. In somecircumstances, the compound is dispersed in microcapsules (microspheres)or nanoparticles prepared from a suitable polymer, for example,5-isobutyl 2-cyanoacrylate (see, for example, Michael et al., J.Pharmacy Pharmacol. 43, 1-5, (1991), and dispersed in a biocompatibledispersing medium, which yields sustained delivery and biologicalactivity over a protracted time.

Pharmaceutical compositions for administering the compound can also beformulated as a solution, microemulsion, or other ordered structuresuitable for high concentration of active ingredients. The vehicle canbe a solvent or dispersion medium containing, for example, water,ethanol, polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycol, and the like), and suitable mixtures thereof.Proper fluidity for solutions can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of a desired particlesize in the case of dispersible formulations, and by the use ofsurfactants. In many cases, it will be desirable to include isotonicagents, for example, sugars, polyalcohols, such as mannitol andsorbitol, or sodium chloride in the composition. Prolonged absorption ofthe compound can be brought about by including in the composition anagent which delays absorption, for example, monostearate salts andgelatin.

In certain embodiments, the compound can be administered in a timerelease formulation, for example in a composition which includes a slowrelease polymer. These compositions can be prepared with vehicles thatwill protect against rapid release, for example a controlled releasevehicle such as a polymer, microencapsulated delivery system orbioadhesive gel. Prolonged delivery in various compositions of thedisclosure can be brought about by including in the composition agentsthat delay absorption, for example, aluminum monostearate hydrogels andgelatin. When controlled release formulations are desired, controlledrelease binders suitable for use in accordance with the disclosureinclude any biocompatible controlled release material which is inert tothe active agent and which is capable of incorporating the compoundand/or other biologically active agent. Numerous such materials areknown in the art. Useful controlled-release binders are materials thatare metabolized slowly under physiological conditions following theirdelivery (for example, at a mucosal surface, or in the presence ofbodily fluids). Appropriate binders include, but are not limited to,biocompatible polymers and copolymers well known in the art for use insustained release formulations. Such biocompatible compounds arenon-toxic and inert to surrounding tissues, and do not triggersignificant adverse side effects, such as nasal irritation, immuneresponse, inflammation, or the like. They are metabolized into metabolicproducts that are also biocompatible and easily eliminated from thebody.

Exemplary polymeric materials for use in the present disclosure include,but are not limited to, polymeric matrices derived from copolymeric andhomopolymeric polyesters having hydrolyzable ester linkages. A number ofthese are known in the art to be biodegradable and to lead todegradation products having no or low toxicity. Exemplary polymersinclude polyglycolic acids and polylactic acids, poly(DL-lacticacidco-glycolic acid), poly(D-lactic acid-co-glycolic acid), andpoly(L-lactic acid-coglycolic acid). Other useful biodegradable orbioerodable polymers include, but are not limited to, such polymers aspoly(epsilon-caprolactone), poly(epsilon-aprolactone-CO-lactic acid),poly(epsilon.-aprolactone-CO-glycolic acid), poly(betahydroxy butyricacid), poly(alkyl-2-cyanoacrilate), hydrogels, such as poly(hydroxyethylmethacrylate), polyamides, poly(amino acids) (for example, L-leucine,glutamic acid, L-aspartic acid and the like), poly(ester urea),poly(2-hydroxyethyl DL-aspartamide), polyacetal polymers,polyorthoesters, polycarbonate, polymaleamides, polysaccharides, andcopolymers thereof. Many methods for preparing such formulations arewell known to those skilled in the art (see, for example, Sustained andControlled Release Drug Delivery Systems, J. R. Robinson, ed., MarcelDekker, Inc., New York, 1978). Other useful formulations includecontrolled-release microcapsules (U.S. Pat. Nos. 4,652,441 and4,917,893), lactic acid-glycolic acid copolymers useful in makingmicrocapsules and other formulations (U.S. Pat. Nos. 4,677,191 and4,728,721) and sustained-release compositions for water-soluble peptides(U.S. Pat. No. 4,675,189).

The pharmaceutical compositions of the disclosure typically are sterileand stable under conditions of manufacture, storage and use. Sterilesolutions can be prepared by incorporating the compound in the requiredamount in an appropriate solvent with one or a combination ofingredients enumerated herein, as required, followed by filteredsterilization. Generally, dispersions are prepared by incorporating thecompound and/or other biologically active agent into a sterile vehiclethat contains a basic dispersion medium and the required otheringredients from those enumerated herein. In the case of sterilepowders, methods of preparation include vacuum drying and freeze-dryingwhich yields a powder of the compound plus any additional desiredingredient from a previously sterile-filtered solution thereof. Theprevention of the action of microorganisms can be accomplished byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Treatment

Disclosed herein are methods of treating a subject with aneurodegenerative disorder through administration of one or more of thedisclosed compounds. The compounds can be administered by anyappropriate route including orally, parenterally, or topically. Inparticular examples, sobetirome, or a pharmaceutically acceptable saltthereof, is administered orally. In certain examples, sobetirome, or apharmaceutically acceptable salt thereof, is administered parenterally.In some embodiments, sobetirome, or a pharmaceutically acceptable saltthereof, is administered buccally, sublingually, sublabially, or byinhalation. In other embodiments, sobetirome, or a pharmaceuticallyacceptable salt thereof, is administered sublingually. In yet otherembodiments, sobetirome, or a pharmaceutically acceptable salt thereof,is administered parenterally. In particular embodiments, sobetirome, ora pharmaceutically acceptable salt thereof, is administeredintra-arterially, intravenously, intraventricularly, intramuscularly,subcutaneously, intraspinally, intraorbitally, intracranially orintrathecally.

The administration of a pharmaceutical composition comprising thedisclosed compounds can be for prophylactic or therapeutic purposes. Forprophylactic and therapeutic purposes, the treatments can beadministered to the subject in a single bolus delivery, via continuousdelivery (for example, continuous transdermal, mucosal or intravenousdelivery) over an extended time period, or in a repeated administrationprotocol (for example, by an hourly, daily or weekly, repeatedadministration protocol). The therapeutically effective dosage of thetreatments for viral infection can be provided as repeated doses withina prolonged prophylaxis or treatment regimen that will yield clinicallysignificant results to alleviate one or more symptoms or detectableconditions associated with a neurodegenerative disorder.

An effective amount or concentration of the disclosed compounds may beany amount of a composition that alone, or together with one or moreadditional therapeutic agents, is sufficient to achieve a desired effectin a subject. The effective amount of the agent will be dependent onseveral factors, including, but not limited to, the subject beingtreated and the manner of administration of the therapeutic composition.In one example, a therapeutically effective amount or concentration isone that is sufficient to prevent advancement, delay progression, or tocause regression of a disease, or which is capable of reducing symptomscaused by any disease, including neurodegenerative disorders.

In one example, a desired effect is to reduce or inhibit one or moresymptoms associated with a neurodegenerative disorder. The one or moresymptoms do not have to be completely eliminated for the composition tobe effective. For example, a composition can decrease the sign orsymptom by a desired amount, for example by at least 20%, at least 50%,at least 80%, at least 90%, at least 95%, at least 98%, or even at least100%, as compared to how the sign or symptom would have progressed inthe absence of the composition or in comparison to currently availabletreatments.

The actual effective amount will vary according to factors such as thetype of neurological disorder to be protected against/therapeuticallytreated and the particular status of the subject (for example, thesubject's age, size, fitness, extent of symptoms, susceptibilityfactors, and the like) time and route of administration, other drugs ortreatments being administered concurrently, as well as the specificpharmacology of treatments for viral infection for eliciting the desiredactivity or biological response in the subject. Dosage regimens can beadjusted to provide an optimum prophylactic or therapeutic response.

An effective amount is also one in which any toxic or detrimental sideeffects of the compound and/or other biologically active agent isoutweighed in clinical terms by therapeutically beneficial effects. Anon-limiting range for a therapeutically effective amount of treatmentsfor viral infection within the methods and formulations of thedisclosure is about 0.0001 μg/kg body weight to about 10 mg/kg bodyweight per dose, such as about 0.0001 μg/kg body weight to about 0.001μg/kg body weight per dose, about 0.001 μg/kg body weight to about 0.01μg/kg body weight per dose, about 0.01 μg/kg body weight to about 0.1μg/kg body weight per dose, about 0.1 μg/kg body weight to about 10μg/kg body weight per dose, about 1 μg/kg body weight to about 100 μg/kgbody weight per dose, about 100 μg/kg body weight to about 500 μg/kgbody weight per dose, about 500 μg/kg body weight per dose to about 1000μg/kg body weight per dose, or about 1.0 mg/kg body weight to about 10mg/kg body weight per dose.

Determination of effective amount is typically based on animal modelstudies followed up by human clinical trials and is guided byadministration protocols that significantly reduce the occurrence orseverity of targeted disease symptoms or conditions in the subject.Suitable models in this regard include, for example, murine, rat,porcine, feline, non-human primate, and other accepted animal modelsubjects known in the art, including the EAE model of multiplesclerosis. Using such models, only ordinary calculations and adjustmentsare required to determine an appropriate concentration and dose toadminister a therapeutically effective amount of the treatments forviral infection (for example, amounts that are effective to alleviateone or more symptoms of a neurodegenerative disorder).

EXAMPLES

The following examples are illustrative of the disclosed compounds. Inlight of this disclosure, those of skill in the art will recognize thatvariations of these examples and other examples of the disclosedcompounds would be possible without undue experimentation.

Example 1—Tert-butyl 2-(4-formyl-3,5-dimethylphenoxy)acetate (Compound3)

To a solution of 4-hydroxy-2,6-dimethylphenol (compound 2) (15.02 g, 100mmol) and DMF (400 mL) was added Cs₂CO₃ (65.2 g, 200 mmol). Theresulting mixture was cooled to 0° C. and t-butyl-chloroacetate (17.9mL, 125 mmol) was slowly added. The reaction mixture was then stirred atroom temperature for 3 hours and subsequently slowly poured into 800 mLH₂O. The resulting solution was stirred for 15 minutes at roomtemperature and then extracted with diethylether (3×500 mL). Thecombined organic fractions were washed with water (3×1 L), brine, driedwith MgSO₄ and concentrated. Recrystallization of the residue withhexanes gave compound 3 (23.6 g, 89%). ¹H NMR (400 MHz, CD₃OD): δ 10.43(s, 1H), 6.65 (s, 2H), 4.65 (s, 2H), 2.58 (s, 6H), 1.49 (s, 9H). HRMSexact mass calcd for C₁₅H₂₁O₄ [M+H]⁺: 265.14344. Found 265.14445.

Example 2—1-(benzyloxy)-4-iodo-2-isopropylbenzene (Compound 5)

To a stirring solution of 2-isopropylphenol (compound 4) (13.62 g, 100mmol), sodium iodide (14.98 g, 100 mmol) and methanol (300 mL), wasadded 10 mL of a 10M NaOH solution. The reaction mixture was then cooledto 4° C. and a solution of NaOCl (6% aq, 129 mL, 115 mmol) was slowlyadded dropwise over 18 hours. The reaction mixture was then allowed tostir at room temperature for 2 hours. A 10% Na₂S₂O₃ solution (300 mL)was added followed by acidification of the solution to neutral pH withconcentrated HCl. The solution was then extracted with diethyl ether(3×300 mL). The combined organic fractions were washed with brine, driedwith MgSO₄ and concentrated. Purification of the residue with flashchromatography (silica, 0% to 75% dichloromethane/hexanes) gave4-iodo-isopropylphenol (19.6 g, 75%). ¹HNMR (400 MHz, CDCl₃) δ (ppm):7.45 (1H, d, j=2 Hz), 7.35 (1H, dd, j=8.4 Hz, 2 Hz), 6.52 (1H, d, J=8.4Hz), 3.14 (1H, septet, J=7.2 Hz), 1.23 (6H, d, J=7.2 Hz). To a solutionof 4-iodo-isopropylphenol (16.18 g, 61.73 mmol) in DMF (200 mL) wasadded K₂CO₃ (25.6 g, 185.2 mmol) and benzyl bromide (92.6 mmol, 11 mL).The reaction mixture was then stirred at 75° C. for 16 hours. Aftercooling the solution the room temperature, the mixture was then slowlypoured into 600 mL of H₂O and subsequently stirred at room temperaturefor 15 min. The mixture was then extracted with hexanes (3×500 mL). Thecombined organic fractions were washed with water (3×500 mL), brine,dried with Mg₂SO₄, and concentrated under reduced pressure. Purificationof the residue with flash chromatography (silica, 0% to 2% ethylacetate/hexanes) yielded compound 5 (16.7 g, 77%). ¹HNMR (400 MHz,CDCl₃): δ 7.41-7.24 (m, 5H), 6.91 (d, 1H, J=2 Hz), 6.76 (d, 1H, J=8.4Hz), 6.63 (m, 3H), 4.97 (s, 2H), 4.58 (s, 2H), 3.89 (s, 2H), 3.30 (sept,1H, J=7.1 Hz), 2.17 (s, 6H), 1.14 (d, 6H, J=7.1 Hz).

Example3—2-(4-(4-(benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic Acid(Compound 6)

A solution of 3 (16.2 g, 46 mmol), THF (180 mL), and 4 Å molecularsieves (3 g) was placed under reduced pressure for 1 minute and thenplaced under argon for 1 minute. This process was repeated three timesto ensure a deoxygenated solution. The solution was then cooled to 0° C.and an iPrMgCl solution (2 M THF, 34.5 mL, 69 mmol) was added. Thereaction mixture was then stirred at room temperature for 2.5 hourswhere it was then cooled to −78° C. A solution of 5 (9.36 g, 35.4 mmol)and THF (20 mL) was then added and the reaction mixture was stirred at−78° C. for 1 hour and at room temperature for 1 hour. The reaction wasquenched with a 10% NH₄Cl (aq) solution (200 mL) and extracted withethyl acetate (3×200 mL). The combined organic fractions were washedwith brine, dried with Mg₂SO₄, and concentrated under reduced pressure.A HNMR was taken to confirm consumption of 5 and the resulting cruderesidue was then utilized in the subsequent reaction. The crude residuewas dissolved in DCM (200 mL) and cooled to 0° C. Triethylsilane (28.3mL, 177 mmol) was added followed by the slow addition of trifluoroaceticacid (40.7 mL, 531 mmol). The reaction mixture was then stirred at roomtemperature for 3 hours and then concentrated with reduced pressure. DCM(100 mL) was added and the solution was concentrated again with reducedpressure. This process was repeated two more times to remove theremaining TFA. Hexanes were added and the resulting mixture was cooledto 0° C. to precipitate the desired product (6) as a white solid (8.15g, 55% (over two steps)). ¹H NMR (400 MHz, CD₃OD): δ 7.41-7.24 (m, 5H),6.91 (d, 1H, J=2 Hz), 6.76 (d, 1H, J=8.4 Hz), 6.63 (m, 3H), 4.97 (s,2H), 4.58 (s, 2H), 3.89 (s, 2 H), 3.30 (sept, 1H, J=7.1 Hz), 2.17 (s,6H), 1.14 (d, 6H, J=7.1 Hz). HRMS exact mass calcd for C₂₇H₃₀O₄Na[M+Na]⁺: m/z 441.20363. Found m/z 441.20463.

Example 4—Representative Procedure for Preparation of Acid Chloride(Compound 6a)

A solution of oxalyl chloride (200 μL 2.33 mmol) in 2 mL of DCM wasslowly added to a 0° C. solution of compound 6 (209 mg, 0.5 mmol) andDCM (4 mL). DMF (2 μL) was then added and the reaction mixture wasstirred at room temperature for 3 hours. The solution was thenconcentrated under reduced pressure. DCM (4 mL) was added to the residueand the solution was concentrated again, this process was repeated oncemore. The crude residue was of sufficient purity and was usedimmediately in the subsequent ester couplings.

Example 5—Ethyl2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl)methyl)-3,5-dimethylphenoxy)Acetate (Compound 7)

To a stirred solution of compound 6 (209 mg, 0.5 mmol) in 2 mL ethanolwas added 1 M HCl (ethanol) (15 mL, 15 mmol). The reaction mixture wasstirred at room temperature for 24 hrs. The solution was then dried withMgSO₄ and concentrated under reduced pressure. The resulting residue wasthen dissolved in 5 mL of methanol and purged with argon. 10% Pd/C (50mg) was added followed by the dropwise addition of triethylsilane (1.01mL, 6.33 mmol). The reaction mixture was stirred at room temperature for3 hrs and then filtered over a pad of celite with methanol. The solutionwas then concentrated under reduced pressure and purified with flashchromatography (silica, 0% to 2% ethyl acetate/hexanes) to yield 7 as anoil (113 mg, 62%). ¹H NMR (400 MHz, CDCl3): δ 6.91 (d, 1H, J=2 Hz), 6.62(s, 2H), 6.60-6.54 (m, 2H), 4.60 (s, 2H), 4.59 (s, 1H), 4.29 (q, 2H,J=7.2 Hz), 3.89 (s, 2H), 3.15 (sept, 1H, J=7.1 Hz), 2.20 (s, 6H), 1.30(t, 3H, J=7.2 Hz), 1.21 (d, 6H, J=7.1 Hz). HRMS exact mass calcd forC₂₂H₂₈O₄Na [M+Na⁺]⁺: m/z 379.18798. Found m/z 379.18823.

Example 6—2-(trimethylamino)ethyl2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetateHydrobromide (Compound 8)

To a solution of 6 (209 mg, 0.5 mmol) dissolved in DMF (5 mL) was addedK₂CO₃ (138 mg, 1.0 mmol) followed by (2-Bromoethyl) trimethylammoniumbromide (309 mg, 1.25 mmol). The reaction mixture was then stirred at rtfor 72 hours and then filtered. The mixture was then directly purifiedwith flash chromatography (silica, 0%, 5%, 10%, 20%, 30% methanol/dcm)to yield the desired product (121 mg). The residue was then dissolved inMeOH (4 mL) and purged with argon. 10% Pd/C (60 mg) was added followedby the dropwise addition of triethylsilane (479 μL, 3 mmol). Thereaction mixture was stirred at room temperature for 4 hrs and thenfiltered over a pad of celite with methanol. The solution was thenconcentrated under reduced pressure and the resulting solid was isolatedwith ether to yield (8) (97 mg, 39% (two steps)). ¹H NMR (400 MHz,CD₃OD): δ 6.82 (d, 1H, J=2 Hz), 6.67 (s, 2H), 6.60 (d, 1H, J=8.2 Hz),6.54 (dd, 1H, J=8.2 Hz, 2 Hz), 4.77 (s, 2H), 4.46 (m, 2H), 3.90 (s, 2H),3.31 (m, 2H), 3.21 (sept, 1H, J=7 Hz), 2.22 (s, 6H), 1.14 (d, 6H, J=7Hz). LRMS (ESI⁺). Found 414.3 (M-Br)⁺.

Example 7—2-(morpholin-4-yl)ethyl2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate(Compound 9)

To a 0° C. solution of 4-(2-hydroxyethyl)morpholine (182 μL, 1.5 mmol),DMAP (122 mg, 1.0 mmol), and DCM (5 mL) was added a solution of 6a (0.5mmol) and DCM (2 mL). The reaction mixture was allowed to warm to rtovernight. The reaction mixture was then concentrated, redissolved in aminimal amount of DCM, and purified using flash chromatography (silica,0% to 4% MeOH/DCM). The resulting ester was then dissolved in 5 mL MeOHand purged with argon. 10% Pd/C (50 mg) was added followed by thedropwise addition of triethylsilane (799 μL, 5 mmol). The reactionmixture was stirred at room temperature for 4 hrs and then filtered overa pad of celite with methanol. The solution was then concentrated underreduced pressure and purified using flash chromatography (silica, 0% to5% MeOH/DCM) to yield 9 as an oil (107 mg, 48% over two steps). ¹H NMR(400 MHz, CDCl₃): δ 6.92 (d, 1H, J=2 Hz), 6.55 (m, 4H), 4.55 (s, 2H),4.36 (t, 2H, J=5.7 Hz), 3.87 (s, 2H), 3.70 (t, 4H, J=4.6 Hz), 3.19(sept, 1H, J=7 Hz), 2.67 (t, 2H, J=5.7 Hz), 2.51 (t, 4H, J=4.6 Hz), 2.18(s, 6H), 1.20 (d, 6H, J=7 Hz). HRMS exact mass calcd for C₂₆H₃₆N₁O₅[M+H⁺]⁺: m/z 442.25880. Found m/z 442.25979.

Example 8—GC1-ethanolamine (Compound 11)

To a 0° C. solution of N-Boc-ethanolamine (161 mg, 1.0 mmol), DMAP (183mg, 1.5 mmol), and DCM (5 mL) was added a solution of compound 6a (0.5mmol) and DCM (2 mL). The reaction mixture was allowed to warm to rtovernight. The reaction mixture was then concentrated, redissolved in aminimal amount of DCM, and purified using flash chromatography (silica,10% to 20% ethyl acetate/hexanes) to yield compound 10 (72%, 0.36 mmol).The resulting ester (compound 10) (200 mg, 0.36 mmol) was dissolved in 4mL MeOH and purged with argon. 10% Pd/C (40 mg) was added followed bythe dropwise addition of triethylsilane (569 μL, 3.56 mmol). Thereaction mixture was stirred at room temperature for 4 hrs and thenfiltered over a pad of celite with methanol. The solution was thenconcentrated under reduced pressure and purified using flashchromatography (silica, 10% to 30% ethyl acetate/hexanes) to thedebenzylated product as an oil (112 mg). The resulting oil (112 mg,0.237 mmol) was dissolved in ethyl acetate (2 mL) and 3 mL of 1 N HCl(ethyl acetate) was added. The reaction mixture was then stirred at roomtemperature overnight, concentrated under reduced pressure, andresulting solid 11 was collected with diethyl ether (75 mg, 51% (overtwo steps)). ¹H NMR (400 MHz, CD₃OD): δ 6.82 (d, 1H, J=2 Hz), 6.67 (s,2H), 6.60 (d, 1H, J=8.2 Hz), 6.54 (dd, 1H, J=8.2 Hz, 2 Hz), 4.77 (s,2H), 4.46 (m, 2H), 3.90 (s, 2H), 3.31 (m, 2H), 3.21 (sept, 1H, J=7 Hz),2.22 (s, 6H), 1.14 (d, 6H, J=7 Hz). HRMS exact mass calcd for C₂₂H₃₀N₁O₄[M-Cl⁻]⁺: m/z 372.21693. Found m/z 372.21807.

Example 9—Benzyl Protected Ethanolamine: (Compound 12)

To a solution of compound 10 (200 mg, 0.356 mmol) in ethyl acetate (2mL) was added 10 mL of 1 N HCl (ethyl acetate). The reaction mixture wasthen stirred at room temperature overnight, concentrated under reducedpressure, and resulting white solid (compound 12) was collected withdiethyl ether (143 mg, 81%). ¹H NMR (400 MHz, CD₃OD): δ 7.45-7.29 (m,5H), 6.92 (d, 1H, J=2 Hz), 6.83 (d, 1H, J=8.4 Hz), 6.71-6.65 (m, 3H),5.03 (s, 2H), 4.78 (s, 2H), 4.47 (t, 2H, J=5 Hz), 3.94 (s, 2H), 3.33 (m,3H), 2.21 (s, 6H), 1.16 (d, 6H, J=7.1 Hz). HRMS exact mass calcd forC₂₂H₃₀N₁O₄ [M-Cl⁻]⁺: m/z 462.26389. Found m/z 462.26450.

Example 10—2-(2,6-diaminohexanamido)ethyl2-(4-{[4-(benzyloxy)-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate(Compound 13)

To a solution of Boc-Lys(Boc)-OH (106 mg, 0.2 mmol) and DMF (2 mL) wasadded EDCl-HCl (38 mg, 0.2 mmol) and HoBt-H₂O (31 mg, 0.2 mmol). Thereaction mixture was stirred at room temperature for 30 min. DIEA (87μL, 0.5 mmol) was added to the reaction mixture followed by compound 11(50 mg, 0.1 mmol) and the reaction mixture was stirred at roomtemperature overnight. The mixture was then poured into H₂O (20 mL) andextracted with ethyl acetate (3×20 mL). The combined organic layers werethen washed with sat. NaHCO₃, 1M HCl, and brine. After drying theorganic layer with MgSO₄, the ethyl acetate was concentrated usingreduced pressure and purified via flash chromatography (silica, 0% to2.5% DCM/MeOH). The residue was dissolved in 4 mL MeOH and purged withargon. 10% Pd/C (100 mg) was added followed by the dropwise addition oftriethylsilane (320 μL, 2 mmol). The reaction mixture was stirred atroom temperature for 4 hrs and then filtered over a pad of celite withmethanol. The methanol solution was then concentrated and hexanes wasadded to the round bottomed flask. A white solid appeared on the wallsof the round bottomed flask, and the resulting hexanes layer wasdecanted. This process was repeated two more times. The resulting solidwas dissolved in 1 mL of ethyl acetate and to this solution was added 4mL of 1M HCl (ethyl acetate). The reaction mixture was stirred at rtovernight and then concentrated using reduced pressure. Diethyl etherwas added and the resulting solid was collected to give compound 13 (23mg, 40%). ¹H NMR (400 MHz, CD₃OD): δ 6.81 (d, 1H, J=2 Hz), 6.67 (s, 2H),6.60 (d, 1H, J=8.2 Hz), 6.52 (dd, 1H, J=8.2 Hz, 2 Hz), 4.73 (s, 2H),4.41 (m, 1H), 4.30 (m, 1H), 3.89 (m, 3H), 3.62 (m, 3H), 3.20 (sept, 1H,J=6.70 Hz), 2.96 (t, 2H, J=7.2 Hz), 2.21 (s, 6H), 1.90 (m, 2H), 1.73 (m,2H), 1.51 (m, 2H), 1.13 (d, 6H, J=6.70 Hz). HRMS exact mass calcd forC₂₈H₄₂N₃O₅ [M-2Cl⁻-H⁺]⁺: m/z 500.31190. Found m/z 500.31243.

Example 11—2-(2-amino-4-methylpentanamido)ethyl2-(2-{[4-(benzyloxy)-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate(Compound 14)

To a solution of (Boc)-Valine-OH (60 mg, 0.274 mmol) and DMF (5 mL) wasadded EDCl-HCl (53 mg, 0.274 mmol) and HoBt-H₂O (42 mg, 0.274 mmol). Thereaction mixture was stirred at room temperature for 30 min. DIEA (119μL, 0.685 mmol) was added to the reaction mixture followed by compound11 (68 mg, 0.137 mmol) and the reaction mixture was stirred at rtovernight. The mixture was then poured into H₂O (30 mL) and extractedwith ethyl acetate (3×30 mL). The combined organic layers were thenwashed with sat. NaHCO₃, 1M HCl, and brine. After drying the organiclayer with MgSO₄, the ethyl acetate was concentrated using reducedpressure and purified via flash chromatography (silica, 50% ethylacetate/hexanes). The residue was dissolved in 3 mL MeOH and purged withargon. 10% Pd/C (30 mg) was added followed by the dropwise addition oftriethylsilane (320 μL, 2 mmol). The reaction mixture was stirred atroom temperature for 4 hrs and then filtered over a pad of celite withmethanol. The methanol solution was then concentrated and purified withflash chromatography (silica, 30% to 50% ethyl acetate/hexanes). Theresulting residue was dissolved in 1 mL of ethyl acetate and to thissolution was added 4 mL of 1M HCl (ethyl acetate). The reaction mixturewas stirred at rt overnight and then concentrated using reducedpressure. Diethyl ether was added and the resulting solid was collectedto give compound 14 (24 mg, 32% overall yield). ¹H NMR (400 MHz, CD₃OD):δ 8.58 (m, 1H), 7.92 (s, 1H), 6.82 (d, 1H, J=2 Hz), 6.66 (s, 2H), 6.60(d, 1H, J=8.2 Hz), 6.54 (dd, 1H, J=8.2 Hz, 2 Hz), 4.70 (s, 2H), 4.33 (m,2H), 3.90 (s, 2H), 3.66 (m, 2H), 3.50 (m, 2H), 3.20 (sept, 1H, J=6.70Hz), 2.21 (s, 6H), 1.14 (d, 6H, J=6.70 Hz), 1.07 (m, 6H). HRMS exactmass calcd for C₂₇H₃₉N₂O₅ [M+H⁺]⁺: m/z 471.28535. Found m/z 471.28686.

Example 12—azetidin-3-yl2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate(Compound 15)

To a 0° C. solution of 1-(tert-butylcarbonyl)-3-hydroxyazetidine (260mg, 1.5 mmol), DMAP (183 mg, 1.5 mmol), and DCM (5 mL) was added asolution of the acid chloride generated from compound 6 (0.5 mmol) andDCM (2 mL). The reaction mixture was allowed to warm to rt overnight.The reaction mixture was then concentrated, redissolved in a minimalamount of DCM, and purified using flash chromatography (silica, 10% to30% ethyl acetate/hexanes). The resulting ester (242 mg, 0.422 mmol) wasdissolved in 5 mL MeOH and purged with argon. 10% Pd/C (90 mg) was addedfollowed by the dropwise addition of triethylsilane (1.01 mL, 6.33mmol). The reaction mixture was stirred at room temperature for 4 hrsand then filtered over a pad of celite with methanol. The solution wasthen concentrated under reduced pressure and purified using flashchromatography (silica, 10% to 30% ethyl acetate/hexanes) to yield thedesired product as an oil (106 mg, 51% over two steps). The resultingresidue was dissolved in ethyl acetate (3 mL) and 5 mL of 1 N HCl (ethylacetate) was added. The reaction mixture was then stirred at roomtemperature overnight, concentrated under reduced pressure, andresulting solid was collected with hexanes. The solid was then purifiedusing flash chromatography (silica, 0% to 10% methanol/(dcm+1%isopropylamine)) to yield compound 15 (101 mg, 45% overall yield). ¹HNMR(400 MHz, CD₃OD): δ 6.80 (d, 1H, J=2 Hz), 6.65 (s, 2H), 6.60 (d, 1H,J=8.2 Hz), 6.52 (dd, 1H, J=8.2 Hz, 2 Hz), 5.44 (m, 1H), 4.78 (s, 2H),4.45 (m, 2H), 4.18 (m, 2H), 3.88 (s, 2H), 3.20 (sept, 1H, J=6.95 Hz),2.20 (s, 6H), 1.13 (d, 6H, J=6.95 Hz). HRMS exact mass calcd forC₂₃H₃₀N₁O₄ [M+H⁺]⁺: m/z 384.21693. Found m/z 384.21735.

Example13—2-amino-3-(4-{[2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetyl]oxy}phenyl)propanoicAcid (Compound 16)

To a solution of N-t-boc-L-tyrosine (281 mg, 1 mmol) and acetone (4 mL)was added 1 N NaOH (aq) (2 mL, 2 mmol). This reaction mixture was thencooled to 0° C. and a solution of the acid chloride generated from(compound 6) (0.5 mmol) and acetone (2 mL) was added dropwise. Thereaction mixture was allowed to warm to r.t. overnight. To the reactionmixture was added 30 mL of 1 N HCl and the mixture was extracted withethyl acetate (3×30 mL). The combined organic layers were then washedwith brine, dried, and concentrated under reduced pressure. The cruderesidue was then purified with flash chromatography (silica, 0% to 5%methanl/dcm+1% acetic acid). The residue was dissolved in 4 mL MeOH andpurged with argon. 10% Pd/C (40 mg) was added followed by the dropwiseaddition of triethylsilane (479 μL, 3 mmol). The reaction mixture wasstirred at room temperature for 4 hrs and then filtered over a pad ofcelite with methanol. The methanol solution was then concentrated andpurified with flash chromatography (silica, 0% to 5% methanl/dcm+1%acetic acid). The resulting residue was dissolved in 2 mL of ethylacetate and to this solution was added 3 mL of 1M HCl (ethyl acetate).The reaction mixture was stirred at rt overnight and then concentratedusing reduced pressure. Diethyl ether was added and the resulting solidwas collected to give compound 16 (33 mg, 12.5% (overall for threesteps)). ¹H NMR (400 MHz, DMSO-D₆): δ 7.32 (d, 2H, J=8.5 Hz), 7.14 (d,2H, J=8.5 Hz), 6.83 (d, 1H, j=2 Hz), 6.71 (s, 2H), 6.61 (d, 1H, J=8.2Hz), 6.46 (dd, 1H, J=8.2, 2 Hz), 5.01 (s, 2H), 4.17 (t, 1H, J=6.5 Hz),3.8 (s, 2H), 3.11 (m, 3H), 2.18 (s, 6H), 1.08 (d, 6H, J=6.8 Hz). HRMSexact mass calcd for C₂₉H₃₄N₁O₆ [M-Cl⁻]⁺: m/z 492.23806. Found m/z492.23738.

Example 14—[(2R,3S,4S,5R,6R)-3,4,5,6-tetrahydroxyoxan-2-yl]methyl2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate(Compound 18)

To a 0° C. solution of 17 (306 mg, 0.566 mmol), DMAP (175 mg, 1.43mmol), and DCM (4 mL) was added a solution of the acid chloridegenerated from 6 (0.714 mmol) and DCM (3 mL). The reaction mixture wasallowed to warm to rt overnight. The reaction mixture was thenconcentrated under reduced pressure and purified with flashchromotography (silica, 10% to 30% ethyl acetate/hexanes) to yield 377mg of purified product. This product (279 mg, 0.296 mmol) was thendissolved in acetic acid (10 mL) and THF (5 mL) and purged with argon.10% Pd/C (300 mg) was added followed by the dropwise addition oftriethylsilane (2.84 mL, 17.8 mmol). The reaction mixture was stirred atroom temperature for 40 hrs and then filtered over a pad of celite withmethanol. The methanol solution was then concentrated under reducedpressure. To this solution (acetic acid remained) was added hexanes andconcentrated again under reduced pressure, this was repeated five moretimes. Lastly, the white solid was collected with hexanes to yield 18(123 mg, 85% (44% overall yield)). ¹H NMR (400 MHz, CD₃OD) δ: 6.82 (d,1H, j=2 Hz), 6.64 (s, 2H), 6.58 (d, 1H, J=8.15 Hz), 6.52 (dd, 1H,J=8.15, 2 Hz), 5.10 (d, 1H, J=3.75 Hz), 4.68 (m, 2H), 4.50 (m, 2H), 4.33(m, 1H), 4.00 (m, 1H), 3.88 (s, 2H), 3.65 (m, 1H), 3.20 (m, 2H), 2.19(s, 6H), 1.29 (d, 2H, J=6.59 Hz), 1.08 (d, 6H, J=6.94 Hz). HRMS exactmass calcd for C₂₆H₃₅N₁O₉ [M+H⁺]⁺: m/z 491.22756. Found m/z 491.22775.

Example 15—2-(dimethylamino)ethyl2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate(Compound 19)

To a 0° C. solution of Dimethylethanolamine (150 uL, 1.5 mmol), DMAP (92mg, 0.5 mmol), NEt₃ (208 uL, 1.5 mmol) and DCM (4 mL) was added asolution of the acid chloride generated from 6 (0.5 mmol) and DCM (5mL). The reaction mixture was allowed to warm to rt overnight. Thereaction mixture was then concentrated under reduced pressure andpurified with flash chromotography (silica, 0% to 5% MeOH/DCM) to yield40 mg of purified product. This product (279 mg, 0.296 mmol) was thendissolved in acetic acid (750 uL) and THF (375 mL) and purged withargon. 10% Pd/C (40 mg) was added followed by the dropwise addition oftriethylsilane (253 mL, 1.59 mmol). The reaction mixture was stirred atroom temperature for 4 hrs and then filtered over a pad of celite. Thesolution was then concentrated under reduced pressure. To this solution(acetic acid remained) was added hexanes and concentrated again underreduced pressure, this was repeated five more times. Lastly, the whitesolid was collected with hexanes to yield 19 (21 mg, (11% overallyield)). ¹HNMR (400 MHz, CDCl₃) δ: 6.94 (d, 1H, J=2 Hz), 6.61 (s, 2H),6.58 (m, 2H), 4.62 (s, 2H), 4.35 (t, 2H, J=5.56 Hz), 3.90 (s, 2H), 3.20(sept, 1H, J=6.82 Hz), 2.66 (t, 2H, J=5.56 Hz), 2.32 (s, 6H), 2.21 (s,6H), 1.23 (d, 2H, J=6.84 Hz). HRMS exact mass calcd for C₂₄H₃₁N₁O₄[M+H⁺]⁺: m/z 400.24824. Found m/z 400.24905.

Example 16—1-methylazetidin-3-yl2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate(Compound 20)

To a 0° C. solution of 1-(tert-butylcarbonyl)-3-hydroxyazetidine (260mg, 1.5 mmol), DMAP (183 mg, 1.5 mmol), and DCM (5 mL) was added asolution of the acid chloride generated from 6 (0.5 mmol) and DCM (2mL). The reaction mixture was allowed to warm to rt overnight. Thereaction mixture was then concentrated, redissolved in a minimal amountof DCM, and purified using flash chromatography (silica, 10% to 30%ethyl acetate/hexanes). The resulting ester was dissolved in DCM (5 mL)and Et₃SiH (80 uL) was added. The solution was then cooled to 0° C. andtreated with TFA (574 uL, 7.5 mmol) and stirred at room temperature for2 hours. The solution was then concentrated under reduced pressure andthe product was precipitated from the solution with diethyl ether toyield the product as a white solid (177 mg, 60%). The isolatedbenzyl-protected intermediate (20a) (40 mg, 0.0681 mmol) was dissolvedin AcOH (1 mL) and paraformaldehyde (41 mg, 1.36 mmol) was addedfollowed by 10% Pd/C (40 mg). To this solution was added Et₃SiH (325 uL,2.04 mmol) dropwise and the reaction mixture was stirred at roomtemperature for 4 hours and filtered over a pad of celite. Ethyl acetatewas added to the solution and the resulting organic layer was washed 2×with sat. NaHCO₃, and 1× with water, followed by Brine. The organiclayer was then dried with MgSO₄ and concentrated under reduced pressure.The product was isolated as a white solid with hexanes (12 mg, 44%).¹HNMR (400 MHz, CDCl₃): δ 6.94 (d, 1H, J=2 Hz), 6.62 (s, 2H), 6.56 (m,2H) 5.18 (p, 1H, J=5.56 Hz), 4.63 (s, 2H), 3.90 (s, 2H), 3.76 (m, 2H),3.20 (m, 3H), 2.41 (s, 3H), 2.22 (s, 6H), 1.23 (d, 6H, J=7.07 Hz). HRMSexact mass calcd for C₂₄H₃₂N₁O₄ [M+H⁺]⁺: m/z 398.23258. Found m/z398.23307.

Example 17—pyrrolidin-2-ylmethyl2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate(Compound 21)

To a 0° C. solution of N-Boc-L-prolinol (252 mg, 1.25 mmol), DMAP (183mg, 1.5 mmol), and DCM (3 mL) was added a solution of 6a (0.25 mmol) andDCM (2 mL). The reaction mixture was allowed to warm to rt overnight.The reaction mixture was then concentrated, redissolved in a minimalamount of DCM, and purified using flash chromatography (silica, 10% to20% ethyl acetate/hexanes) to yield the coupled N-boc ester. Theresulting ester was dissolved in 4 mL MeOH and purged with argon. 10%Pd/C (50 mg) was added followed by the dropwise addition oftriethylsilane (599 uL, 3.75 mmol). The reaction mixture was stirred atroom temperature for 4 hrs and then filtered over a pad of celite withmethanol. The solution was then concentrated under reduced pressure andpurified using flash chromatography (silica, 10% to 30% ethylacetate/hexanes) to yield the debenzylated product as an oil. Theresulting oil was dissolved in ethyl acetate (2 mL) and Et₃SiH (0.25mmol, 40 uL) was added followed by 1 N HCl (ethyl acetate) (4 mL). Thereaction mixture was then stirred at room temperature overnight,concentrated under reduced pressure, and resulting solid 11 wascollected with diethyl ether (52 mg, 47% (over three steps)). ¹HNMR (400MHz, CDCl₃): δ 6.94 (d, 1H, J=2 Hz), 6.62 (s, 2H), 6.61 (d, 1H, J=8.08Hz), 6.55 (dd, 1H, J=8.08 Hz, 2.02 Hz), 4.66 (m, 2H), 4.27 (m, 1H), 3.91(s, 2H), 3.76-3.50 (m, 4H), 3.19 (sept, 1H, J=6.82 Hz), 2.23 (s, 6H),2.11-1.86 (m, 3H), 1.65 (m, 1H), 1.23 (d, 6H, J=6.82 Hz). HRMS exactmass calcd for C₂₅H₃₄N₁O₄ [M+H⁺]⁺: m/z 412.24824. Found 412.24878 m/z.

Example 18—3-methyazetidin-3-yl2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate(Compound 22)

Followed procedure for the synthesis of (21) except with1-Boc-3-Hydroxy-3-methylazetidine, THF, and heating during the couplingstep (45° C.) yielded a white solid (22 mg, 22% overall yield). ¹HNMR(400 MHz, CDCl₃): δ 6.94 (d, 1H, J=2 Hz), 6.62 (m, 3H), 6.51 (dd, 1H,J=8.08 Hz, 2.02 Hz), 4.64 (m, 2H), 4.35 (br, 2H), 4.10 (br, 2H), 3.90(s, 2H), 3.18 (sept, 1H, J=7.07 Hz), 2.22 (s, 6H), 1.81 (s, 3H), 1.22(d, 6H, J=6.82 Hz). HRMS exact mass calcd for C₂₄H₃₂N₁O₄ [M+H⁺]⁺: m/z398.23258. Found m/z 398.23363.

Example 19—piperidin-4-yl2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate(Compound 23)

Followed procedure for the synthesis of (21) except with1-Boc-4-hydroxypiperidine and yielded a white solid (52 mg, 50% overallyield). ¹HNMR (400 MHz, CDCl₃): δ 6.94 (d, 1H, J=2 Hz), 6.62 (s, 2H),6.55 (d, 1H, J=8.08 Hz), 6.52 (dd, 1H, J=8.08 Hz, 2.02 Hz), 5.03 (sept,1H, J=4.4 Hz), 4.62 (s, 2H), 3.90 (s, 2H), 3.21 (sept, 1H, J=6.82 Hz),3.05 (m, 2H), 2.74 (m, 2H), 2.22 (s, 6H), 1.94 (m, 2H), 1.62 (m, 2H),1.23 (d, 6H, J=6.82 Hz). HRMS exact mass calcd for C₂₅H₃₄N₁O₄ [M+H⁺]⁺:m/z 412.24824. Found m/z 412.24886.

Example 20—piperidin-3-yl2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate(Compound 24)

Followed procedure for the synthesis of (21) except with1-Boc-3-hydroxypiperidine and yielded a white solid (37 mg, 36% overallyield). ¹H NMR (400 MHz, CDCl₃): δ 6.94 (d, 1H, J=2 Hz), 6.61 (s, 2H),6.52 (d, 1H, J=8.08 Hz), 6.49 (dd, 1H, J=8.08 Hz, 2.02 Hz), 4.95 (m,1H), 4.60 (d, 2H, J=1.52 Hz), 3.87 (s, 2H), 3.22 (sept, 1H, J=7.07 Hz),3.02 (dd, 1H, J=13 Hz, 2.78 Hz)), 2.87 (dd, 1H, J=13.14 Hz, 5.81 Hz),2.80 (t, 2H, J=5.05 Hz), 2.20 (s, 6H), 1.88 (m, 1H), 1.81-1.68 (m, 2H),1.51 (m, 1H), 1.21 (d, 6H, J=6.82 Hz). HRMS exact mass calcd forC₂₅H₃₄N₁O₄ [M+H⁺]⁺: m/z 412.24824. Found m/z 412.24845.

Example 21—1-amino-2-methlpropan-2-yl2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate(Compound 25)

To a 0° C. solution of N-Cbz-1-amino-2-methylpropan-2-ol (223 mg, 1mmol), DMAP (92 mg, 0.75 mmol), and THF (3 mL) was added a solution of6a (0.25 mmol) and THF (2 mL). The reaction mixture was allowed stir at45° C. overnight. The reaction mixture was then concentrated,redissolved in a minimal amount of DCM, and purified using flashchromatography (silica, 20% to 50% ethyl acetate/hexanes) to yield thecoupled N-Cbz ester (37 mg, 0.059 mmol). The resulting ester wasdissolved in 2 mL MeOH and 2 mL of THF and purged with argon. 10% Pd/C(50 mg) was added followed by the dropwise addition of triethylsilane(283 uL, 1.77 mmol). The reaction mixture was stirred at roomtemperature for 3 hrs and then filtered over a pad of celite withmethanol. The solution was then concentrated under reduced pressure andprecipitated with hexanes and ether to yield the product as an oilyresidue (5.6 mg, 5.6% overall). ¹HNMR (400 MHz, CDCl₃): δ 7.04 (m, 1H),6.94 (d, 1H, J=2 Hz), 6.66 (s, 2H), 6.62 (d, 1H, J=8.08 Hz), 6.54 (dd,1H, J=8.08 Hz, 2.02 Hz), 5.06 (br, 1H), 4.55 (s, 2H), 3.92 (s, 2H), 3.38(d, 2H, J=6.32 Hz), 3.19 (sept, 1H, J=6.82 Hz), 2.23 (s, 6H), 2.20 (br,1H), 1.25 (s, 6H), 1.23 (d, 6H, J=6.82 Hz). HRMS exact mass calcd forC₂₄H₃₄N₁O₄ [M+H⁺]⁺: m/z 400.24824. Found m/z 400.24765.

Example 22—3-(trifluoromethyl)azetidin-3-yl2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate(Compound 26)

To a 0° C. solution ofN-Cbz-1-amino-3-hydroxy-3-(trifluoromethyl)-azetidine HCl (250 mg, 1.41mmol), DMAP (122 mg, 1 mmol), and THF (3 mL) was added a solution of 6a(0.25 mmol) and THF (2 mL). The reaction mixture was allowed stir at 45°C. overnight. The reaction mixture was then concentrated, redissolved ina minimal amount of DCM, and purified using flash chromatography(silica, 20% to 50% ethyl acetate/hexanes) to yield the coupled N-Cbzester (75 mg, 0.121 mmol). The resulting ester was dissolved in 2 mLMeOH and 2 mL of THF and purged with argon. 10% Pd/C (50 mg) was addedfollowed by the dropwise addition of triethylsilane (484 uL, 3.03 mmol).The reaction mixture was stirred at room temperature for 3 hrs and thenfiltered over a pad of celite with methanol. The solution was thenconcentrated under reduced pressure and precipitated with hexanes andether to yield the product as an oily residue (6.8 mg, 6.0% overall).¹HNMR (400 MHz, CD₃OD): δ 6.82 (d, 1H, J=2 Hz), 6.67 (s, 2H), 6.59 (d,1H, J=8.08 Hz), 6.52 (dd, 1H, J=8.08 Hz, 2.02 Hz), 4.78 (br s, 4H), 3.90(s, 2H), 3.62 (t, 2H, J=5.86 Hz), 3.21 (sept, 1H, J=7.02 Hz), 2.21 (s,6H), 1.23 (d, 6H, J=7.02 Hz).

Example23—2-((2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetoxy)methyl)piperidin-1-iumChloride (Compound 27)

To a 0° C. solution of1-(tert-butylcarbonyl)-2-(hydroxymethyl)piperidine (296 mg, 1.25 mmol),DMAP (183 mg, 1.5 mmol), and DCM (6 mL) was slowly added a solution ofthe acid chloride generated from 6 (0.5 mmol) in 4 mL DCM. The reactionmixture was allowed to warm to room temperature overnight with stirring.Evaporation of the resulting mixture gave a light-yellow oil which waspurified using flash chromatography (silica, 10% to 30% ethylacetate/hexanes). The resulting ester (288 mg, 0.468 mmol, 94% yield)was dissolved in 5 mL of dry methanol with 1 mL THF and 10% Pd/C (100mg) was added to generate a suspension. The reaction mixture wassubjected to vacuum for approximately 1 min, then placed under argon forapproximately 1 min. This process was repeated three times to ensure themixture was properly degassed. Triethylsilane (1.2 mL, 7.53 mmol) wasthen added dropwise to the suspension and the reaction mixture wasstirred for 4 hrs at room temperature. Filtration over a pad of celitewith methanol, concentration in vacuo, and purification via flashchromatography (silica, 10% to 30% ethyl acetate/hexanes) gave thedesired product as an oil (129 mg, 0.245 mmol, 52% yield). The productoil (129 mg, 0.245 mmol) was dissolved in 5 mL ethyl acetate and 3 mL of1 N HCl in ethyl acetate was added, followed by the addition oftriethylsilane (39 n, 0.245 mmol). The reaction mixture was stirredovernight at room temperature, concentrated under vacuum, andprecipitated with hexanes to give the product 27 as a white solid (92mg, 0.199 mmol, 81% yield, 40% overall yield). ¹H NMR (400 MHz, CD₃OD):δ 6.76 (s, 1H), 6.61 (s, 2H), 6.53 (d, 1H, J=8.6 Hz), 6.48 (d, 1H, J=7.6Hz), 4.74 (s, 2H), 4.38 (dd, 1H, J=12.4 Hz, J=3.2 Hz), 4.25 (dd, 1H,J=12.1 Hz, J=1.7 Hz), 3.84 (s, 2H), 3.41 (m, 1H), 3.16 (m, 2H), 2.99(sept, 1H, J=6.8 Hz), 2.16 (s, 6H), 1.89 (m, 2H), 1.56 (m, 2H), 1.08 (d,6H, J=6.6 Hz). HRMS exact mass calcd for C₂₆H₃₆N₁O₄ [M+H⁺]⁺: m/z426.26389. Found m/z 426.26465.

Example 24—(R)-1-aminopropan-2-yl2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate (Compound28)

To a 0° C. solution of benzyl (R)-(2-hydroxypropyl)carbamate (262 mg,1.25 mmol), DMAP (183 mg, 1.5 mmol), and THF (8 mL) was slowly added asolution of the acid chloride generated from 6 (0.5 mmol) in 4 mL THF.The reaction mixture was allowed to warm to room temperature, thenheated to 50° C. overnight with stirring. Filtration and evaporation ofthe resulting filtrate gave a light-yellow oil which was purified usingflash chromatography (silica, 10% to 30% ethyl acetate/hexanes). Theresulting ester (50 mg, 0.082 mmol, 17% yield) was dissolved in 5 mL ofdry methanol with 1 mL THF and 10% Pd/C (40 mg) was added to generate asuspension. The reaction mixture was subjected to vacuum forapproximately 1 min, then placed under argon for approximately 1 min.This process was repeated three times to ensure the mixture was properlydegassed. Triethylsilane (0.4 mL, 2.51 mmol) was then added dropwise tothe suspension and the reaction mixture was stirred for 4 hrs at roomtemperature. Filtration over a pad of celite with methanol andconcentration in vacuo gave an oily residue which was precipitated withcold hexanes and washed with hexanes to give the desired product as awhite solid (22 mg, 0.057 mmol, 68% yield, 12% overall yield). ¹H NMR(400 MHz, CD₃OD): δ 6.77 (s, 1H), 6.62 (s, 2H), 6.55 (d, 1H, J=8.11 Hz),6.45 (d, 1H, J=8.22 Hz), 5.20 (m, 1H, J=3.0 Hz), 4.71 (d, 2H, J=8.2 Hz),3.84 (s, 2H), 3.21 (sept, 1H, J=6.8 Hz), 3.18 (m, 2H), 2.16 (s, 6H),1.31 (d, 3H, J=6.5 Hz), 1.09 (d, 6H, J=6.99 Hz). HRMS exact mass calcdfor C₂₃H₃₂N₁O₄ [M+H⁺]⁺: m/z 386.23258. Found m/z 386.23349.

Example 25—(S)-1-aminopropan-2-yl2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate (Compound29)

To a 0° C. solution of benzyl (S)-(2-hydroxypropyl)carbamate (262 mg,1.25 mmol), DMAP (183 mg, 1.5 mmol), and THF (8 mL) was slowly added asolution of the acid chloride generated from 6 (0.5 mmol) in 4 mL THF.The reaction mixture was allowed to warm to room temperature, thenheated to 50° C. overnight with stirring. Filtration and evaporation ofthe resulting filtrate gave a light-yellow oil which was purified usingflash chromatography (silica, 10% to 30% ethyl acetate/hexanes). Theresulting ester (101 mg, 0.166 mmol, 33% yield) was dissolved in 5 mL ofdry methanol with 1 mL THF and 10% Pd/C (80 mg) was added to generate asuspension. The reaction mixture was subjected to vacuum forapproximately 1 min, then placed under argon for approximately 1 min.This process was repeated three times to ensure the mixture was properlydegassed. Triethylsilane (0.82 mL, 5.15 mmol) was then added dropwise tothe suspension and the reaction mixture was stirred for 4 hrs at roomtemperature. Filtration over a pad of celite with methanol andconcentration in vacuo gave an oily residue which was precipitated withcold hexanes and washed with hexanes to give the desired product as awhite solid (59 mg, 0.153 mmol, 90% yield, 30% overall yield). ¹H NMR(400 MHz, CD₃OD): δ 6.77 (s, 1H), 6.61 (s, 2H), 6.54 (d, 1H, J=8 Hz),6.48 (d, 1H, J=8.3 Hz), 5.19 (m, 1H, J=3 Hz), 4.70 (d, 2H, J=4 Hz), 3.84(s, 2H), 3.19 (m, 2H), 3.16 (sept, 1H, J=6.8 Hz), 2.16 (s, 6H), 1.31 (d,3H, J=6.4 Hz), 1.09 (d, 6H, J=6.9 Hz). HRMS exact mass calcd forC₂₃H₃₂N₁O₄ [M+H⁺]⁺: m/z 386.23258. Found m/z 386.23287.

Example 26—3-amino-1,1,1-trifluoropropan-2-yl2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate (Compound30)

To a 0° C. solution of benzyl (3,3,3-trifluoro-2-hydroxypropyl)carbamate(207 mg, 0.786 mmol), DMAP (120 mg, 0.982 mmol), and chloroform (8 mL)was slowly added a solution of the acid chloride generated from 6 (0.392mmol) in 4 mL chloroform. The reaction mixture was allowed to warm toroom temperature, then heated to 50° C. overnight with stirring.Evaporation of the product mixture gave a light-yellow oil which waspurified using flash chromatography (silica, 10% to 30% ethylacetate/hexanes). The resulting ester (79 mg, 0.119 mmol, 30% yield) wasdissolved in 5 mL of dry methanol with 1 mL THF and 10% Pd/C (80 mg) wasadded to generate a suspension. The reaction mixture was subjected tovacuum for approximately 1 min, then placed under argon forapproximately 1 min. This process was repeated three times to ensure themixture was properly degassed. Triethylsilane (0.6 mL, 3.77 mmol) wasthen added dropwise to the suspension and the reaction mixture wasstirred for 4 hrs at room temperature. Filtration over a pad of celitewith methanol and concentration in vacuo gave an oily residue which wasprecipitated with cold hexanes and washed with hexanes to give thedesired product as a white solid (39 mg, 0.089 mmol, 75% yield, 23%overall yield). ¹H NMR (400 MHz, CD₃OD): δ 6.78 (s, 1H), 6.59 (s, 2H),6.55 (d, 1H, J=8.1 Hz), 6.48 (d, 1H, J=8.4 Hz), 4.64 (s, 2H), 4.28 (m,1H), 3.84 (s, 2H), 3.23 (dd, 1H, J=13.1 Hz, J=3.2 Hz), 3.17 (sept, 1H,J=6.9 Hz), 3.04 (dd, 1H, J=13.2 Hz, J=9.5 Hz), 2.15 (s, 6H), 1.09 (d,6H, J=7 Hz).

Example 27—2-(methylamino)ethyl2-(4-(4-hydroxy-3-methylbenzyl)-3,5-dimethylphenoxy)acetateHydrochloride (Compound 31)

To a 0° C. solution of benzyl (2-hydroxyethyl)(methyl)carbamate (314 mg,1.5 mmol), DMAP (183 mg, 1.5 mmol), and THF (8 mL) was slowly added asolution of the acid chloride generated from 6 (0.5 mmol) in 4 mL THF.The reaction mixture was allowed to warm to room temperature, thenheated to 50° C. overnight with stirring. Filtration and evaporation ofthe resulting filtrate gave a light-yellow oil which was purified usingflash chromatography (silica, 10% to 30% ethyl acetate/hexanes). Theresulting ester (146 mg, 0.239 mmol, 48% yield) was dissolved in 5 mL ofdry methanol with 1 mL THF and 10% Pd/C (100 mg) was added to generate asuspension. The reaction mixture was subjected to vacuum forapproximately 1 min, then placed under argon for approximately 1 min.This process was repeated three times to ensure the mixture was properlydegassed. Triethylsilane (1.2 mL, 7.53 mmol) was then added dropwise tothe suspension and the reaction mixture was stirred for 4 hrs at roomtemperature. Filtration over a pad of celite with methanol andconcentration in vacuo gave an oily residue which was precipitated withcold hexanes and washed with hexanes. The resulting residue wasdissolved in 3 mL of ethyl acetate and 1 mL of 1 N HCl (ethyl acetate)was added and stirred 3 hrs. Evaporation of the solvent, followed bywashing with hexanes gave the desired product as a white solid (37 mg,0.088 mmol, 37% yield, 18% overall yield). ¹H NMR (400 MHz, CD₃CN): δ8.87 (bs, 1H), 6.91 (s, 1H), 6.68 (s, 2H), 6.64 (d, 1H, J=8.1 Hz), 6.53(d, 1H, J=7.8 Hz), 4.79 (s, 2H), 4.48 (m, 2H), 3.86 (s, 2H), 3.20 (m,2H), 3.17 (sept, 1H, J=6.9 Hz), 2.60 (s, 3H), 2.19 (s, 6H), 1.13 (d, 6H,J=7.0 Hz). HRMS exact mass calcd for C₂₃H₃₂N₁O₄ [M+H⁺]⁺: m/z 386.23258.Found m/z 386.23259.

Example 28—1-aminopropan-2-yl2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate (Compound32)

Followed procedure for the synthesis of (22) except withN-boc-1-amino-2-propanol and yielded an oil (2.2 mg, 0.0052 mmol, 2.1%):¹H NMR (methanol-d₄, 400.2 MHz) δ 6.75 (s, 1H), 6.54 (m, 3H), 6.47 (dd,1H, 1=2.0, 6.0 Hz), 5.18 (m, 1H), 4.69 (d, 2H, 1=4.8 Hz), 3.84 (s, 2H),3.15 (m, 3H), 2.15 (s, 6H), 1.30 (d, 3H, J=6.4 Hz), 1.07 (d, 6H, 1=6.8Hz). HRMS exact mass calcd for C₂₃H₃₂N₁O₄ [M+H⁺]⁺: m/z 386.23258. Foundm/z 386.23308.

Example 29—1-(dimethylamino)propan-2-yl2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate (Compound33)

A round bottom flask with a stirring bar and DCM (12 mL) is charged with6 (669 mg, 1.6 mmol, 1 eq). It was cooled to 0° C. with an ice-bath andDMF (2 μL) was added to it. A solution of oxalyl chloride (640 μL, 7.45mmol, 4.66 eq) in DCM (6 mL) was added to it dropwise. The reactionmixture was stirred at room temperature for 3 hours. The reactionmixture was then concentrated under reduced pressure and most of theexcess oxalyl chloride was removed by repeated evaporation with DCM(2×10 mL). The crude acid chloride thus prepared was then dissolved indry THF (5 mL) and slowly added to a 0° C. solution of1-Dimethylamino-2-propanol (783 μL, 6.46 mmol) and DMAP (525 mg, 4.30mmol) in THF (25 mL). The reaction mixture was then allowed to warm upat room temperature and refluxed overnight. It was then cooled, filteredand concentrated. The crude mixture was purified by flash chromatography(silica, 0% to 5% MeOH/DCM) to yield the pure benzyl protected GC1ester. The resulting protected ester (150 mg, 0.298 mmol) was dissolvedin a mixture of THF and MeOH (1:10). 10% Pd/C (30 mg, 0.2 eq) was addedto it followed by the dropwise addition of triethylsilane (684 μL, 4.47mmol). After stirring at room temperature for 2 hours, the reactionmixture was filtered over a bed of celite and concentrated. Purificationon silica using flash chromatography and 0% to 5% MeOH in DCM as theeluent gave the dimethyl propanol-GC1 ester 33 (25 mg, 20%). 1H NMR (400MHz, CD3CN):

6.92 (d, 1H, J=1.84 Hz), 6.60 (m, 4H), 5.25 (m, 1H), 4.66 (m, 3H), 3.89(s, 2H), 3.15 (m, 1H), 2.34 (s, 6H), 2.12 (s, 6H), 1.29 (d, 3H, J=6.4Hz), 1.21 (d, 6H, J=6.8 Hz). LRMS for C₂₅H₃₅NO₄ [M+H⁺]⁺: m/z 414.3.Found m/z 414.9.

Example 30—1-(1H-imidazol-1-yl)propan-2-yl2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate (Compound34)

A stirring solution of 6 (100 mg, 0.239 mmol, 1 eq) in DCM (0.5 mL) atroom temperature is treated with oxalyl chloride (125 μL, 1.43 mmol, 6eq) and 1 drop of DMF. The reaction stirs for 3 hours followed byremoval of the solvent under reduced pressure. The crude intermediate isdissolved in DCM (3 mL), which is subsequently removed under reducedpressure. The remainder oxalyl chloride was removed by repeatedevaporation with DCM (2×10 mL). The crude intermediate acyl chloride istreated with DCM (1 mL) followed by triethylamine (65 μL, 0.478 mmol, 2eq) and 2-(1H-imidazol-1-yl)propan-1-ol (72 mg, 0.57 mmol, 2.4 eq).2-(1H-imidazol-1-yl)propan-1-ol was synthesized as previously describedin Borowiecki, P. et al. Beilstein J Org Chem, 9, 516-525 (2013). Thereaction stirs overnight at room temperature and is then purifieddirectly by flash chromatography (0-5% MeOH in DCM) and dried under highvacuum to give the intermediate ester as a viscous oil (78 mg, 62%). Astirring solution of this intermediate ester (78 mg, 0.148 mmol, 1 eq)in degassed THF:MeOH (1:1, 1 mL) under argon is treated with 10% Pd/C(20 mg) followed by dropwise addition of triethylsilane (70 mg, 0.59mmol, 4 eq). The reaction stirs for 3 hours at room temperature. Thereaction solution is filtered through a pad of celite, which issubsequently washed with MeOH. The filtrate is concentrated and thenpurified by flash chromatography (0-10% MeOH in DCM) to give the product34 as a white solid (32 mg, 50%). ¹H NMR (400 MHz, Chloroform-d) δ 7.28(b, 1H), 7.06 (s, 1H), 6.93 (d, J=2 Hz, 1H), 6.89 (s, 1H), 6.60 (m, 4H),5.3 (m, 1H), 4.60 (s, 2H), 4.09 (m, 2H), 3.90 (s, 2H), 3.23 (sept,J=6.9, 1H), 2.22 (s, 6H), 1.25 (m, 9H). LRMS (ESI) m/z (M+H⁺) C₂₆H₃₃N₂O₄calculated 436.2, found 436.7.

Example 31—1-amino-1-oxopropan-2-yl2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate (Compound35)

A stirring solution of 6 (270 mg, 0.646 mmol, 1 eq) in DCM (4 mL) at 0°C. is treated with oxalyl chloride (221 μL, 2.58 mmol, 4 eq) and 1 dropof DMF. The reaction is warmed to room temperature and stirs for 3 hoursfollowed by removal of the solvent under reduced pressure. The crudereaction is dissolved in DCM (10 mL), which is subsequently removedunder reduced pressure. The remainder oxalyl chloride was removed byrepeated evaporation with DCM (2×10 mL). The crude intermediate acylchloride is treated with DCM (1 mL) followed by triethylamine (270 μL,1.94 mmol, 3 eq), lactamide (115 mg, 1.31 mmol, 2 eq), and DMAP (8 mg,0.065 mmol, 0.1 eq). The reaction stirs overnight at room temperatureand is then purified directly by flash chromatography (0-5% MeOH in DCM)and dried under high vacuum to give the intermediate ester as a viscousoil (256 mg, 81%). A stirring solution of this ester (47 mg, 0.148 mmol,1 eq) in degassed MeOH (1 mL) under argon is treated with 5% Pd/C (10mg) followed by dropwise addition of triethylsilane (145 mg, 1.25 mmol,13 eq). The reaction stirs for 3 hours at room temperature. The reactionsolution is filtered through a pad of celite, which is subsequentlywashed with MeOH. The filtrate is concentrated and then purified byflash chromatography (0-5% MeOH in DCM) to give the product 35 as awhite solid (27 mg, 70%). ¹H NMR (400 MHz, Chloroform-d) δ 6.95 (d, J=2Hz, 1H), 6.60 (m, 4H), 5.82 (b, 1H), 5.35 (q, J=6.9 Hz, 1H), 5.23 (b,1H), 4.78 (b, 1H), 4.75 (s, 2H), 3.91 (s, 2H), 3.18 (sept, J=6.9 Hz,1H), 2.22 (s, 6H), 1.54 (d, J=6.9 Hz, 3H), 1.23 (d, J=7 Hz, 6H). LRMS(ESI) m/z (M+Na⁺) C23H29NO5Na requires 422.2, found 422.0.

Example 32—1-hydroxypropan-2-yl2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate (Compound36)

A mixture of 6 (200 mg, 0.477 mmol, 1 eq) and 1-(benzyloxy)propan-2-ol(475 mg, 2.86 mmol, 6 eq) are treated neat with sulfuric acid (1 drop).1-(benzyloxy)propan-2-ol was synthesized as previously described inAikawa, K. et al. J Am Chem Soc, 134, 10329-10332 (2012). The reactionstirs for 3 days at room temperature. The crude reaction mixture isdiluted with DCM (3 mL) and purified by flash chromatography (0-40%EtOAc in hexanes). The product is concentrated and dried under highvacuum to give the intermediate ester as a viscous oil (236 mg, 88%). Astirring solution of this ester (200 mg, 0.352 mmol, 1 eq) under argonis treated with 10% Pd/C (40 mg) and triethylsilane (340 μL, 2.12 mmol,6 eq) is added dropwise. The reaction stirs at room temperature for 3hours. The reaction solution is filtered through a pad of celite, whichis subsequently washed with MeOH. The filtrate is concentrated and thenpurified by flash chromatography (0-5% MeOH in DCM) to give the product36 that solidifies upon exposed to air (77 mg, 56%). The isolatedproduct was shown to be a mixture of 1- and 2-hydroxypropanylregioisomers (3:1); the characterization of only the major isomer isshown. ¹H NMR (400 MHz, Chloroform-d) δ 6.93 (d, J=2 Hz, 1H), 6.60 (m,4H), 5.15 (qd, J=6.5 Hz, 3.3 Hz, 1H), 4.66 (s, 2H), 4.58 (s, 1H), 4.13(b, 1H), 3.91 (s, 2H), 3.69 (m, 2H), 3.16 (sept, J=6.9 Hz, 1H), 2.22 (s,6H), 1.249 (m, 9H). LRMS (ESI) m/z (M+Na⁺) C23H30O5Na calculated 409.2,found 408.7.

Example 33—3-methyl-1-(methylamino)butan-2-yl2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate (Compound37)

To a 0° C. solution of 1-(benzyl(methyl)amino)-3-methylbutan-2-ol (530mg, 2.56 mmol), DMAP (312 mg, 2.55 mmol), and THF (8 mL) was slowlyadded a solution of the acid chloride generated from 6 (0.66 mmol) in 4mL THF. The reaction mixture was allowed to warm to room temperature,then heated to reflux overnight with stirring. Filtration andevaporation of the resulting filtrate gave a light-yellow oil which waspurified using flash chromatography (silica, 10% to 50% ethylacetate/hexanes). The resulting ester (200 mg, 0.329 mmol, 50% yield)was dissolved in 5 mL of dry methanol with 1 mL THF and 10% Pd/C (100mg) was added to generate a suspension. The reaction mixture wassubjected to vacuum for approximately 1 min, then placed under argon forapproximately 1 min. This process was repeated three times to ensure themixture was properly degassed. Triethylsilane (1.6 mL, 10.04 mmol) wasthen added dropwise to the suspension and the reaction mixture wasstirred for 4 hrs at room temperature. Filtration over a pad of celitewith methanol and concentration in vacuo gave an oily residue which wasprecipitated with cold hexanes and washed with hexanes. The desiredproduct was obtained as a white solid after drying under high vacuum(101 mg, 0.236 mmol, 72% yield, 36% overall yield). ¹H NMR (400 MHz,CD₃CN): δ 6.93 (s, 1H), 6.71 (s, 2H), 6.69 (d, 1H, J=8.6 Hz), 6.54 (dd,1H, J=8.3 Hz, J=2.2 Hz), 5.22 (m, 1H), 5.12 (d, 1H, J=16.5 Hz), 4.77 (d,1H, J=16.5 Hz), 3.88 (s, 2H), 3.18 (m, 3H), 2.62 (s, 3H), 2.20 (s, 6H),1.15 (d, 6H, J=6.8 Hz), 0.93 (dd, 6H, J=7 Hz, J=2.1 Hz). LRMS (ESI) m/zC₂₆H₃₇NO₄ calculated (M+H⁺) 428.3, found 428.7.

Example 34—1-amino-3-methylbutan-2-yl2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate (Compound38)

To a 0° C. solution of 1-(dibenzylamino)-3-methylbutan-2-ol (745 mg,2.63 mmol), DMAP (321 mg, 2.63 mmol), and THF (8 mL) was slowly added asolution of the acid chloride generated from 6 (0.66 mmol) in 4 mL THF.The reaction mixture was allowed to warm to room temperature, thenheated to reflux overnight with stirring. Filtration and evaporation ofthe resulting filtrate gave a light-yellow oil which was purified usingflash chromatography (silica, 10% to 50% ethyl acetate/hexanes). Theresulting ester (128 mg, 0.187 mmol, 28% yield) was dissolved in 5 mL ofdry methanol with 1 mL THF and 10% Pd/C (100 mg) was added to generate asuspension. The reaction mixture was subjected to vacuum forapproximately 1 min, then placed under argon for approximately 1 min.This process was repeated three times to ensure the mixture was properlydegassed. Triethylsilane (1.35 mL, 8.47 mmol) was then added dropwise tothe suspension and the reaction mixture was stirred for 4 hrs at roomtemperature. Filtration over a pad of celite with methanol andconcentration in vacuo gave an oily residue which was precipitated withcold hexanes and washed with hexanes. The desired product was obtainedas a white solid after drying under high vacuum (69 mg, 0.167 mmol, 89%yield, 25% overall yield). ¹H NMR (400 MHz, CD₃CN): δ (s, 1H), 6.69 (s,2H), 6.66 (d, 1H, J=8.5 Hz), 6.53 (dd, 1H, J=8.1 Hz, J=2.5 Hz), 5.12 (m,1H), 5.03 (d, 1H, J=16.3 Hz), 4.75 (d, 1H, J=16.5 Hz), 3.87 (s, 2H),3.18 (m, 3H), 2.20 (s, 6H), 1.15 (d, 6H, J=6.8 Hz), 0.92 (dd, 6H, J=6.8Hz, J=1.7 Hz). LRMS (ESI) m/z C25H35NO4 calculated (M+H⁺): 414.3, found:414.4.

1-15. (canceled)
 16. A method of treating a neurodegenerative disorderin a subject, comprising administering a pharmaceutical composition tothe subject, wherein the pharmaceutical composition comprises: one ormore pharmaceutically acceptable carriers; and an effective amount of acompound with the structure:

or any pharmaceutically acceptable salt thereof, where R₁ isheteroalkyl, substituted heteroalkyl, substituted cycloalkyl,heterocycloalkyl, substituted heterocycloalkyl, substituted aryl,heteroaryl, or substituted heteroaryl.
 17. A method of treating aneurodegenerative disorder in a subject, comprising administering apharmaceutical composition to the subject, wherein the pharmaceuticalcomposition comprises: one or more pharmaceutically acceptable carriers;and an effective amount of a compound with the structure:

or any pharmaceutically acceptable salt thereof where R₁ is lysinyl,valinyl, phenylalaninyl, glucosyl, or


18. A method of treating a neurodegenerative disorder in a subject,comprising administering a pharmaceutical composition to the subject,wherein the pharmaceutical composition comprises: one or morepharmaceutically acceptable carriers; and an effective amount of acompound with the structure:

or any pharmaceutically acceptable salt thereof where R₁ is substitutedalkylamino, cycloalkylamino, or substituted cycloalkylamino.
 19. Amethod of treating a neurodegenerative disorder in a subject, comprisingadministering a pharmaceutical composition to the subject, wherein thepharmaceutical composition comprises: one or more pharmaceuticallyacceptable carriers; and an effective amount of a compound with thestructure:

or any pharmaceutically acceptable salt thereof wherein R₁ isethylamino, ethyl(N,N,N)-trimethylamino, ethylmorpholinyl,ethyl(N,N)-dimethylamino, 3-(N-methyl)azetidinyl, 4-pyrrolidinyl,3-pyrrolidinyl, 2,2-dimethylethylamino, 3-(3-trifluoromethyl)azetidinyl,2-pyrrolidinyl, 2-methylethylamino, 2-trifluoromethylamino,N-methyl-ethylamino, 1-methyl-(N,N)-dimethylethylamino,1-methyl-2-imazodinylethylamino; 1-methyl-2-keto-ethylamino,1-isopropyl-ethylamino, or 1-isopropyl-N-methyl-ethylamino.
 20. Themethod of claim 19, wherein R₁ is 2-methylethylamino further comprisingR and S enantiomers.
 21. The method of claim 19, wherein the compoundhas the structure:

and wherein the compound is a halide salt.
 22. The method of claim 21,wherein the pharmaceutically acceptable halide salt of the compound hasthe structure:


23. The method of claim 19, wherein the compound has the structure:

or any pharmaceutically acceptable salt thereof.
 24. A method oftreating a neurodegenerative disorder in a subject, comprisingadministering a pharmaceutical composition to the subject, wherein thepharmaceutical composition comprises: one or more pharmaceuticallyacceptable carriers; and an effective amount of a compound, wherein thecompound is 2-(dimethylamino)ethyl2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate;1-methylazetidin-3-yl2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate;pyrrolidin-2-ylmethyl2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate;3-methyazetidin-3-yl2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate;piperidin-4-yl2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate;piperidin-4-yl2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate;1-amino-2-methlpropan-2-yl2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate;3-(trifluoromethyl)azetidin-3-yl2-(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5-dimethylphenoxy)acetate;2-((2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetoxy)methyl)piperidin-1-iumchloride; (R)-1-aminopropan-2-yl2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate;(S)-1-aminopropan-2-yl2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate;2-(methylamino)ethyl2-(4-(4-hydroxy-3-methylbenzyl)-3,5-dimethylphenoxy)acetatehydrochloride; 1-aminopropan-2-yl2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate;1-(dimethyl amino)propan-2-yl2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate;1-(1H-imidazol-1-yl)propan-2-yl2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate;1-amino-1-oxopropan-2-yl2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate;1-hydroxypropan-2-yl2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate;3-methyl-1-(methylamino)butan-2-yl2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate; or1-amino-3-methylbutan-2-yl 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate, or any pharmaceutically acceptable saltthereof.
 25. A method of treating a neurodegenerative disorder in asubject, comprising administering to the subject an effective amount ofa compound with the structure:


26. A method of treating a neurodegenerative disorder in a subject,comprising administering to the subject an effective amount of acompound with the structure:


27. The method of any one of claims 16 to 26, wherein theneurodegenerative disorder is X-linked adrenoleukodystrohy or multiplesclerosis.